Holzapfel-Meyers-Nicolaou modification of the Hantzsch thiazole synthesis

Article abstract of DOI:10.1055/s-2007-990851

Modified conditions for Hantzsch thiazole synthesis provides valine- and threonine-derived thiazoles without significant loss of optical purity. This two- or three-step procedure proceeds by the cyclocondensation of the corresponding thioamide under basic conditions, according to modified methods of Meyers and Holzapfel. The hydroxythiazoline intermediate is then dehydrated by treatment with trifluoroacetic anhydride-pyridine, followed by triethylamine, according to Nicolaou's procedure. Solvolysis of the trifluoroacetamide derivative produced in this process can be affected with sodium ethoxide in ethanol to give a reliable method for the stereoselective synthesis of functionalised thiazole building blocks in high yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990851

PAPER
3535
Holzapfel–Meyers–Nicolaou Modification of the Hantzsch Thiazole Synthesis
H
olzapfel–Mey
l
e
olaou
H
an
a
tzschThiaz
n
ole Synthesi
o
s
r A. Merritt, Mark C. Bagley*
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20874030; E-mail: Bagleymc@cardiff.ac.uk
Received 2 August 2007
total synthesis of such natural products is dependent upon
Abstract: Modified conditions for Hantzsch thiazole synthesis pro-
vides valine- and threonine-derived thiazoles without significant
loss of optical purity. This two- or three-step procedure proceeds by
the cyclocondensation of the corresponding thioamide under basic
the ability to prepare amino acid derived thiazoles in high
yield and enantiomeric purity. The Hantzsch synthesis of
thiazoles by reaction of an amino acid derived thioamide
conditions, according to modified methods of Meyers and Holz- with an a-bromocarbonyl compound at reflux in ethanol is
apfel. The hydroxythiazoline intermediate is then dehydrated by
treatment with trifluoroacetic anhydride–pyridine, followed by tri-
known to result in epimerisation at the a-stereogenic cen-
tre as a result of the concomitant formation of one equiv-
ethylamine, according to Nicolaou’s procedure. Solvolysis of the
alent of hydrogen bromide (Scheme 1).
trifluoroacetamide derivative produced in this process can be affect-
ed with sodium ethoxide in ethanol to give a reliable method for the
stereoselective synthesis of functionalised thiazole building blocks
in high yield.
R
R
Br–
CO2Et
H
N+
H
N
BocHN
Br–
BocHN
Br
CO2Et
Key words: Hantzsch, thiazoles, heterocycles, amino acids
H
S
S
H
R
Amino acid derived thiazoles are a common motif in
many families of biologically active natural products such
as the thiopeptide antibiotics (1 and 2, Figure 1),1 patella-
mides such as 3,2 and nostocyclamide (4).3 The successful
N
S
BocHN
CO2Et
Scheme 1 Racemisation in the Hantzsch thiazole synthesis
HO
HN
O
NH2
O
O
N
S
S
N
O
N
HN
H
NH
O
S
N
N
N
S
N
N
O
S
S
H
O
Me
NH
O
H
O
O
N
N
HN
N
H
OH
S
N
H
H
HN
N
S
N
H
Me
Me
H
O
O
O
Me
HO
HN
N
H
O
N
N
HO
H
H
O
H
O
NH
S
N
N
NH
H
O
O
micrococcin P1 (2)
HN
H
O
S
OH
O
Me
O
Me
OH
H
H
S
N
H
N
N
H
S
O
H
thiostrepton A (1)
N
N
N
N
Me
H
S
N
HO
N
O
Me
H
S
HN
NH
OH
N
O
O
NH
HN
H
N
O
N
S
O
O
O
(+)-nostocyclamide (4)
patellamide E (3)
Figure 1 Thiopeptide antibiotics and other heterocyclic natural products containing amino acid derived thiazoles
SYNTHESIS 2007, No. 22, pp 3535–3541
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.10.2007
DOI: 10.1055/s-2007-990851; Art ID: P09507SS
© Georg Thieme Verlag Stuttgart · New York

3536
E. A. Merritt, M. C. Bagley
PAPER
Recent years have seen a number of attempts to adapt the These procedures were revisited by Nicolaou and co-
Hantzsch thiazole synthesis for use with substrates prone workers during their landmark total synthesis of thiostrep-
to racemisation.4 In 1990, Holzapfel et al. reported a mod- ton (1).7 Nicolaou et al. used higher reaction temperatures
ification of the standard reaction conditions and success- than those used in the Meyers method, and employed py-
fully prepared amino acid derived thiazoles in high ridine instead of 2,6-lutidine; treatment with trifluoroace-
enantiomeric purity by using a lower reaction temperature tic anhydride (TFAA) in the presence of pyridine,
and basic reaction conditions.4a A key feature of the mod- followed by triethylamine, effected the elimination. These
ified Hantzsch thiazole synthesis is the formation of the reaction conditions led to N-trifluoroacetylation of any
hydroxythiazoline intermediate 6 and addition of reagents free NH groups in the target molecule and so subsequent
to activate 6, facilitating the necessary elimination to fur- treatment with sodium ethoxide in ethanol was necessary
nish thiazole 7 (Scheme 2). Further studies by Meyers et in order to liberate the desired product.
al. examined the effect of using different reagents to elim-
inate the intermediate hydroxythiazoline to form the de-
sired thiazole product. The reaction was conducted at
Valine-derived thiazole 7 was a key building block in our
synthetic efforts towards micrococcin P1 (2)8 and so, with
a number of different literature procedures available to ef-
–40 °C to –20 °C and the experimental procedure differed
fect the desired transformation, an investigation into the
significantly from the Holzapfel method in the isolation of
most reliable method for its synthesis was undertaken. To
6 and removal of the heterogeneous base prior to the elim-
this end, thiovalinamide 5 was prepared according to es-
ination step.4b These conditions have been successfully
tablished methods5a and submitted, in turn, to the reported
utilized in the landmark synthesis of several heterocyclic
conditions for modified Hantzsch thiazole synthesis, ex-
natural products and their analogues in recent years,5 in-
amining in each case the yield and optical purity of the
cluding nostocyclamide,5a the promothiocins,5b the Lisso-
product 7 (Scheme 2, Table 1). The acidic reaction condi-
clinum cyclic peptides5c and more recently, GE2270A.5d
tions of the traditional Hantzsch reaction (entry 1) were
clearly inappropriate for substrate 5, whereas the Holz-
apfel (entry 2) and Meyers (entries 3 and 4) modifications
did provide the product 7, but either in low yield on a
However, it is apparent from a study by Pattenden et al.
that whilst these modified Hantzsch procedures constitute
an extremely valuable route to optically pure thiazoles,
the conditions of Meyers can prove to be problematic, in
small scale (entries 2 and 3) or compromised optical puri-
particular when larger quantities of products are required.6
ty (entry 4) when 1.0 g of 5 was used. These findings are
in agreement with Pattenden’s previous observations.6
O
Nicolaou’s modified conditions (entry 5), whilst not being
investigated previously for the synthesis of 7, did deliver
the product, but without complete stereocontrol and only
after solvolysis of the trifluoroacetamide 8, which was the
sole product of this procedure.
Br
CO2Et
NH2
N
CO2Et
OH
BocHN
BocHN
– HBr
step 1
S
S
5
6
As the three methods given in Table 1 failed to provide a
satisfactory and reproducible route to thiazole 7 both in
terms of yield and enantiomeric excess, it was decided
that further modifications to the reaction conditions
should be investigated. The Meyers and Nicolaou condi-
tions were the main focus of these subsequent studies.
Modification of Nicolaou’s conditions by changing the
base used for dehydration of intermediate 6, led to the iso-
N
N
BocHN
BocN
F3C
CO2Et
CO2Et
– H2O
step 2
S
S
O
7
8
Scheme 2 Formation of valine-derived thiazoles 7 and 8
Table 1 Application of Literature Methodology to the Synthesis of Thiazole 7
Step 1
Step 2
Entry Method
Quantity of 5 (g) Solvent
Temp (°C)
reflux
Base
Temp (°C)
Reagents
Yield (%) eea (%)
1
2
3
4
5
Hantzsch
Holzapfel
Meyers
EtOH
–
reflux
–
0b
33
–
0.050
0.22
1.0
DME
DME
DME
DME
0
KHCO3
KHCO3
KHCO3
NaHCO3
0
TFAA, 2,6-Lu
TFAA, 2,6-Lu
TFAA, 2,6-Lu
TFAA, py, Et3N
>98
>98
88
–40 to –20
–40 to –20
r.t.
–40 to –20
–40 to –20
0
9
59
Meyers
Nicolaou
0.3
85c
88c
a The ee values were determined by HPLC on a chiral stationary phase, using a ChiralPac AD column, flow rate 1 mL min–1; i-PrOH:hexane,
5:95; detected at 269 nm.
b No product was isolated, probably as a consequence of HBr-catalysed Boc deprotection and subsequent loss of the product during work-up
and purification.
c Only 8 was isolated; ee value was determined following subsequent solvolysis to 7.
Synthesis 2007, No. 22, 3535–3541 © Thieme Stuttgart · New York

PAPER
Holzapfel–Meyers–Nicolaou Hantzsch Thiazole Synthesis
3537
Table 2 Modified Procedures for the Synthesis of 7
Step 1
Step 2
Entry
Solvent
DME
Temp (°C)
r.t.
Base
Temp (°C)
Reagents
Yield (%)
88b
eea (%)
1
2
NaHCO3
KHCO3
0
TFAA, 2,6-Lu, Et3N
TFAA, 2,6-Lu
91b
DME
–18
–18
97c
>98
a The ee values were determined by HPLC. See Table 1 footnote a, for conditions.
b Isolated 7 (18% yield, 91% ee) and 8 (70% yield, 91% ee); the ee value for 8 was determined following subsequent solvolysis to 7.
c Only 8 was isolated; the ee value was determined following subsequent solvolysis to 7.
lation of a 1:4 mixture of the desired product 7 and the N-
trifluoroacetyl derivative 8 (Table 2, entry 1), both in 91%
ii
i
NH2
N
7
CO2Et
OH
ee. The Meyers modification of the Hantzsch thiazole
synthesis was then performed at –18 °C rather than
–40 °C, and resulted in a dramatic increase in yield from
59% to 97% but curiously delivered the trifluoroacet-
amide 8. However, treatment of 8 with sodium ethoxide in
ethanol, according to Nicolaou’s procedure, led to the iso-
lation of 7 as a single enantiomer.7 Although the length of
the sequence had been increased, this approach proved to
be a reliable and high-yielding route to optically pure 7.
BocHN
BocHN
S
S
5
6
Scheme 3 Reagents and conditions: (i) ethyl bromopyruvate,
KHCO3, DME, r.t., 2 h; (ii) See Table 3.
Table 3 Reaction Conditions for the Methanesulfonyl Chloride–
Triethylamine Mediated Synthesis of Thiazole 7 from Hydroxy-
thiazoline 6
With a method in hand for the synthesis of chiral thiazoles
in excellent yield and enantiomeric purity, the reagents
used to dehydrate the intermediate hydroxythiazoline 6
were varied in order to circumvent the formation of N-tri-
fluoroacetyl thiazole 8 and thus remove the need for a sub-
sequent solvolysis step. The use of methanesulfonyl
chloride and triethylamine in the dehydration of alcohols
is a well documented and reliable procedure, so these re-
agents were applied to the dehydration of 6 (Scheme 3,
Table 3). Reacting 5 with ethyl bromopyruvate, in the
presence of solid potassium hydrogen carbonate at room
temperature, gave hydroxythiazoline 6, which was then
treated with methanesulfonyl chloride and triethylamine
as described in Table 3. It is worthy of note that thiazole 7
can be prepared as a single enantiomer following dehydra-
tion, even when 6 is prepared at room temperature. This
finding demonstrates that, under basic conditions, racemi-
sation in the Hantzsch thiazole synthesis occurs in the
elimination step of the procedure. Addition of methane-
sulfonyl chloride and triethylamine to 6 at room tempera-
ture and stirring for one hour, afforded 7 in 70% yield and
38% ee (entry 1). The probable cause of the observed ra-
cemisation was the exothermic reaction, which occurred
on addition of methanesulfonyl chloride and triethyl-
amine and caused the reaction temperature to reach up to
90 °C. Repetition of the reaction with addition of the re-
agents to 6 at 0 °C, prevented the exotherm and the reac-
tion temperature increased by only 7 °C. The product was
found to be optically pure, but the yield was drastically re-
duced (entry 2). Purification of the reaction mixture by
aqueous work-up further reduced the yield (entry 3). In-
creasing the reaction time to 48 hours was unsuccessful in
improving the yield of the process (entry 4).
Entry MsCl
(equiv)
Temp (°C) Time (h) Work-up Yield (%)ee (%)
1
2
1.1
1.1
1.1
1.1
1.1
2
r.t.
1
2
no
no
yes
no
no
no
no
no
no
no
70
33
15
21
35
28
36
68
68
26
38
>98
>98
>98
92
0→r.t.
0→r.t.
0→r.t.
0
3
2
4
48
5
3.5
60
2+1
6
0→r.t.
r.t.
>98
38
7
5
8
10
r.t.
2+1
0.5
0.5
36
9a
10b
10
10
–1
12
–1
>98
a Reaction conducted using a CEM Discover® Coolmate apparatus,
with concurrent irradiation and cooling.
b Reaction conducted under thermal conditions.
of methanesulfonyl chloride and prolonged reaction times
(60 h, entry 6), afforded a slight improvement in yield
over those described in entry 4. Addition of five equiva-
lents of methanesulfonyl chloride, stirring for two hours,
then addition of triethylamine resulted in a poor yield and
low optical purity (entry 7); increasing to 10 equivalents
methanesulfonyl chloride, gave a moderate yield of 7, also
with low optical purity. Having limited success with im-
proving the yield of the reaction by increasing the reaction
time, the effect of microwave irradiation at low tempera-
ture with concurrent heating and cooling9 was investigat-
ed.10 Hydroxythiazoline 6 was formed by irradiation of a
mixture of 5, ethyl bromopyruvate and potassium hydro-
gen carbonate in 1,2-dimethoxyethane (DME) for 20 min-
From these results, it was clear that the exothermic reac-
tion responsible for racemisation was necessary to im-
prove the yield of the reaction. The use of two equivalents
Synthesis 2007, No. 22, 3535–3541 © Thieme Stuttgart · New York

3538
E. A. Merritt, M. C. Bagley
PAPER
utes at –20 °C with an initial power of 300 W, using a In conclusion, a range of conditions have been investigat-
CEM Discover® CoolMate Sub-Ambient microwave syn- ed for the conversion of amino acid derived thioamides
thesizer. The mixture was then treated as shown in into thiazoles without racemisation. While previously re-
Table 3 (entry 9). Irradiation at –1 °C for 30 minutes, af- ported conditions for this transformation have been found
forded thiazole 7 in 68% yield, however, the enantiomeric to be unreliable, modifications to the temperature and re-
excess was only 12%. Finally, the CoolMate reaction was agents used have provided insight into the causes of race-
repeated under thermal conditions (entry 10) and fur- misation in the Hantzsch thiazole synthesis and enabled
nished 7 as a single enantiomer in 26% yield. As no suit- the preparation of chiral thiazole building blocks with
able method for the synthesis of enantiopure thiazoles in complete stereocontrol and in excellent yield.
high yield had been discovered, the reaction was attempt-
ed using p-toluenesulfonyl chloride as the activating
Commercially available reagents were used without further purifi-
agent. However, no thiazole was formed under any of the
conditions investigated. Reactions utilizing triflic anhy-
dride also failed due to polymerisation of the solvent. On
the basis of these findings it was concluded that the most
efficient route to enantiopure valine-derived thiazole 7
was via trifluoroacetamide 8, using the conditions shown
in Table 2, entry 2.
cation; solvents were dried by standard procedures. Petroleum ether
(PE), where used, had a boiling range of 40–60 °C. Flash chroma-
tography was carried out using Merck Kieselgel 60 H silica or
Matrex silica 60. Analytical thin layer chromatography was carried
out using aluminium-backed plates coated with Merck Kieselgel 60
GF254 that were visualised under UV light (at 254 and/or 360 nm).
Melting points (mp) were determined on a Kofler hot stage appara-
tus and are uncorrected. IR spectra were recorded in CH2Cl2 for sol-
id samples or as a thin film between NaCl plates for liquid samples,
in the range 4000–600 cm–1 on a Perkin–Elmer 1600 series FTIR
During our work towards the synthesis of the central het-
erocyclic domain of micrococcin P1 (2), it was necessary
to prepare threonine-derived thiazole 13 (Scheme 4).8 The
formation of 13 from thioamide 12 was investigated under
a range of conditions (Table 4). Meyers’ original condi-
tions failed to give the desired product (entry 1); the meth-
anesulfonyl chloride–triethylamine conditions furnished
13 in only 21% yield (entry 2). Nicolaou’s original condi-
tions afforded thiazole 13 as a single diastereoisomer in
good yield (entry 3). The lack of a free NH in thiazole 13
eliminates the possibility of formation of an N-trifluoro-
acetyl derivative, as observed in the valine example
(Scheme 2), making Nicolaou’s reaction conditions par-
ticularly useful for such substrates and our adopted meth-
od of choice.
1
spectrometer and are reported in cm–1. H NMR spectra were re-
corded at 400 MHz in CDCl3 at 25 °C, unless otherwise stated, us-
ing a Bruker DPX 400, Bruker DRX 500 or Bruker Avance 250
instrument and are reported in ppm. In vacuo refers to evaporation
at reduced pressure using a rotary evaporator and diaphragm pump,
followed by the removal of trace volatiles using a vacuum (oil)
pump.
(S)-N-tert-(Butoxycarbonyl)valinamide
To a stirred solution of N-Boc-(S)-valine (3.00 g, 13.81 mmol) and
Et3N (1.94 mL, 1.41 g, 13.94 mmol, 1.01 equiv) in anhydrous THF
(120 mL) at 0 °C, was added ethyl chloroformate (1.33 mL, 1.51 g,
13.94 mmol, 1.01 equiv) and the mixture stirred for 1 h. Aqueous
NH3 (35%, 10 mL) was added and the solution was allowed to warm
to r.t. and stirred for 1 h. The organic solvent was removed in vacuo
and the resulting aqueous solution was diluted with H2O (10 mL)
and extracted with EtOAc (3 × 50 mL). The combined organic ex-
tracts were washed sequentially with sat. aq NaHCO3 (50 mL),
citric acid (1 M, 50 mL), brine (50 mL), dried (Na2SO4) and
evaporated in vacuo to yield the title compound.
9
R = CO2H
O
HO
i
ii
R
N
10 R = CONH2
CO2H
O
BocHN
Boc
iii
iv
11 R = CN
Yield: 2.83 g (95%); colourless solid; mp 159–161 °C (EtOAc)
(Lit.11 160–161 °C); [a]D20 17.0 (c 1.00, MeOH) [Lit.12 17.7 (c 1.33,
DMF)].
HRMS: m/z [M + H+] calcd for C10H21N2O3: 217.1547; found:
v
N
CO2Et
12 R = CSNH2
N
Boc
S
13
217.1546.
Scheme 4 Reagents and conditions: (i) 2,2-dimethoxypropane,
PPTS, THF, reflux, 16 h, 99%; (ii) EtOC(O)Cl, Et3N, 0 °C, 1 h then
35% aq NH3, r.t., 24 h, 77%; (iii) POCl3, pyridine, 0 °C, 3 h, 78%; (iv)
(NH4)2S, MeOH, r.t., 24 h, 99%; (v) ethyl bromopyruvate, NaHCO3,
DME, r.t., 24 h; then pyridine, TFAA, 0 °C, 2 h, then Et3N, 74%.
IR (CH2Cl2): 3385, 3342, 3191, 2921, 1681, 1657, 1519, 1461,
1377, 1245, 1170, 1044, 1019, 899, 878, 775, 722 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.05 (1 H, br s, exch. D2O, NH),
5.72 (1 H, br s, exch. D2O, NH), 5.05 (1 H, br d, exch. D2O, NH),
3.90 (1 H, dd, J = 7.9, 7.9 Hz, a-CH), 2.08 (1 H, m, (CH3)2CH),
1.38 [9 H, s, C(CH3)3], 0.92 (3 H, d, J = 6.8 Hz, CH3CHCH3), 0.88
(3 H, d, J = 6.8 Hz, CH3CHCH3),
Table 4 Synthesis of Thiazole 13 from Thioamide 12
13C NMR (100 MHz, CDCl3): d = 175.0 (C), 156.1 (C), 80.1 (C),
Entry
Method
Yield (%)
59.4 (CH), 30.8 (CH), 28.3 (CH3), 19.3 (CH3), 17.8 (CH3).
1
2
3
Meyers
0
21
74
MS (APCI): m/z (%) = 217 (90) [M + H+], 161 (100), 151 (15), 149
(57), 139 (10), 129 (22).
MsCl–Et3Na
Nicolaou
(S)-N-tert-(Butoxycarbonyl)thiovalinamide (5)
(S)-N-tert-(Butoxycarbonyl)valinamide (2.00 g, 9.25 mmol, 1
equiv) was dissolved in anhydrous CH2Cl2 (120 mL). Lawesson’s
reagent (1.87 g, 4.62 mmol, 0.5 equiv) was added and the resulting
solution was heated at reflux for 16 h. The solvent was evaporated
a Reagents and conditions: Ethyl bromopyruvate, NaHCO3, DME, r.t.,
24 h; then MsCl (10 equiv, r.t., 16 h), Et3N (r.t., 4 h).
Synthesis 2007, No. 22, 3535–3541 © Thieme Stuttgart · New York

PAPER
Holzapfel–Meyers–Nicolaou Hantzsch Thiazole Synthesis
3539
in vacuo and the residue was dissolved in EtOAc (100 mL) and
washed with sat. aq NaHCO3 (100 mL). The organic layer was dried
(Na2SO4) and evaporated in vacuo and the residue was purified by
column chromatography (PE–Et2O, 3:7) to give the title compound.
was added and the solution was stirred for 1 min then cooled to
0 °C. A solution of TFAA (125 mL, 0.89 mmol, 4 equiv) and 2,6-
lutidine (0.22 mL, 1.87 mmol, 8.5 equiv) in DME (1 mL) was added
and the reaction mixture was allowed to reach r.t. before evapora-
tion in vacuo. The residue was partitioned between CHCl3 (10 mL)
and H2O (10 mL) and the organic layer was dried (Na2SO4) and
evaporated in vacuo. Purification on silica (PE, Et2O, 2:1) afforded
the title compound.
Yield: 1.33 g (62%); yellow foam; mp 84–85 °C (PE–Et2O) (Lit.13
112–113 °C); [a]D –46.7 (c 0.3, CHCl3) [Lit.13 –43.5 (c 0.7,
26
CHCl3)]; Rf = 0.30 (PE–Et2O, 3:7).
HRMS: m/z [M + H+] calcd for C10H21N2O2S: 233.1318; found:
233.1319.
Yield: 24 mg (33%); pale-yellow solid; ee >98%.
IR (CH2Cl2): 3317, 3146, 2923, 2853, 1684, 1509, 1456, 1366,
1298, 1237, 1164, 1045, 1011, 870, 763, 718 cm–1.
(S)-Ethyl 2-{1-[N-(tert-butoxycarbonyl)-2,2,2-trifluoroacet-
amido]-2-methylpropyl}thiazole-4-carboxylate (8)
1H NMR (400 MHz, CDCl3): d = 8.20 (1 H, br s, exch. D2O, NH),
7.70 (1 H, br s, exch. D2O, NH), 5.24 (1 H, d, J = 8.9 Hz, exch. D2O,
NH), 4.13 (1 H, m, a-CH), 2.10 [1 H, m, (CH3)2CH], 1.37 [9 H, s,
C(CH3)3], 0.92 [6 H, pseudo d, J = 5.9 Hz, CH(CH3)2].
13C NMR (100 MHz, CDCl3): d = 209.5 (C), 156.0 (C), 80.3 (C),
65.2 (CH), 33.3 (CH), 28.4 (CH3), 19.6 (CH3), 18.3 (CH3).
KHCO3 (2.36 g, 23.6 mmol, 8 equiv) was added to a solution of (S)-
tert-butyl 1-amino-3-methyl-1-thioxobutan-2-ylcarbamate (684
mg, 2.94 mmol) in anhydrous DME (7 mL) and the solution was
cooled to –18 °C. Ethyl bromopyruvate (1.11 mL, 1.72 g, 8.83
mmol, 3 equiv) was filtered through a pad of Celite® and the pad
was washed with Et2O (7 mL). The combined filtrates were evapo-
rated in vacuo and the residue was dissolved in anhydrous DME (7
mL) and cooled to –18 °C. A solution of TFAA (1.67 mL, 2.48 g,
11.78 mmol, 4 equiv) and 2,6-lutidine (3.09 mL, 2.84 g, 26.50
mmol, 9 equiv) in anhydrous DME (4 mL) was added and the reac-
tion mixture was stirred at –18 °C for 30 min. The solvent was evap-
orated in vacuo and the residue was dissolved in CHCl3 (20 mL) and
washed with H2O (20 mL). The aqueous layer was further extracted
with CHCl3 (20 mL) and the combined organic extracts were
washed with H2O (20 mL) and brine (20 mL), dried (Na2SO4) and
evaporated in vacuo. Purification of the residue by column chroma-
tography (PE–EtOAc, 3:1) afforded the title compound.
MS (APCI): m/z (%) = 233 (18) [M + H+], 177 (100), 133 (75).
(S)-Ethyl 2-[1-(tert-Butoxycarbonylamino)-2-methylpropyl]thi-
azole-4-carboxylate (7); Meyers Method4b
KHCO3 (1.72 g, 17.2 mmol, 4 equiv) was added to a solution of (S)-
N-tert-(butoxycarbonyl)thiovalinamide (1.00 g, 4.3 mmol) in anhy-
drous DME (10 mL) at –40 °C. Ethyl bromopyruvate (2.32 mL,
3.61 g, 18.5 mmol, 3 equiv) was added and the solution was stirred
for 16 h at –20 °C. The mixture was allowed to warm to r.t., filtered
through a pad of Celite® and the pad was washed with Et2O (10 mL).
The filtrate was evaporated in vacuo and the residue was dissolved
in anhydrous DME (10 mL). The solution was cooled to –40 °C and
a solution of TFAA (2.01 mL, 2.98 g, 14.2 mmol, 3.3 equiv) and
2,6-lutidine (3.46 mL, 3.18 g, 29.7 mmol, 6.9 equiv) in anhydrous
DME (5 mL) was added. The reaction mixture was stirred at –20 °C
for 30 min then evaporated in vacuo, the residue was dissolved in
CHCl3 (100 mL) and washed with H2O (100 mL). The aqueous lay-
er was further extracted with CHCl3 (50 mL) and the combined or-
ganic extracts were washed with H2O (100 mL) and brine (100 mL),
dried (Na2SO4) and evaporated in vacuo. Purification of the residue
by column chromatography (PE–EtOAc, 3:1) afforded the title
compound.
Yield: 1.21 g (97%); yellow oil; Rf = 0.30 (PE–EtOAc, 3:1).
HRMS: m/z [M + H+] calcd for C17H24N2O5F3S: 425.1358; found:
425.1361.
IR (CH2Cl2): 2970, 2925, 1713, 1649, 1508, 1369, 1237, 1202,
1168, 1097, 1017 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12 (1 H, s, 5-H), 5.39 (1 H, d,
J = 10.9 Hz, a-CH), 4.34 (2 H, q, J = 7.1 Hz, OCH2CH3), 2.78 [1 H,
m, (CH3)2CH], 1.43 [9 H, s, C(CH3)3], 1.31 (3 H, t, J = 7.1 Hz,
OCH2CH3), 0.95 (3 H, d, J = 6.6 Hz, CH3CHCH3), 0.92 (3 H, d,
J = 6.6 Hz, CH3CHCH3).
13C NMR (125 MHz, CDCl3): d = 173.2 (C), 161.4 (C), 155.2 (C),
147.4 (C), 126.8 (CH), 86.9 (C), 61.4 (CH2), 58.0 (CH), 33.3 (CH),
28.3 (CH3), 27.4 (CH3), 19.4 (CH3), 14.4 (CH3). Signals for F3CCO
and F3CCO not observed.
Yield: 0.83 g (59%); colourless solid; mp 114–116 °C (EtOAc–PE)
23
(Lit.5a 114–115 °C); [a]D –36.2 (c 1.00, CHCl3) [Lit. for (R)-
enantiomer5a +41.6 (c 1.06, CHCl3)]; ee 88%; Rf = 0.28 (PE–
EtOAc, 3:1).
MS (ES+): m/z (%) = 425 (3) [M + H+], 325 (58), 273 (100), 196
(30), 180 (8).
HRMS: m/z [M + H+] calcd for C15H25N2O4S: 329.1530; found:
329.1532.
IR (CH2Cl2): 3300, 3094, 2922, 2853, 1713, 1699, 1456, 1379,
1339, 1305, 1232, 1174, 1104, 1084, 1031, 999, 878, 777, 718 cm–1.
(S)-Ethyl 2-[1-(tert-Butoxycarbonylamino)-2-methylpropyl]thi-
azole-4-carboxylate (7)
1H NMR (400 MHz, CDCl3): d = 8.01 (1 H, s, 5-H), 5.25 (1 H, d,
J = 7.7 Hz, exch. D2O, NH), 4.85 (1 H, dd, J = 7.7, 7.7 Hz, a-CH),
4.35 (2 H, q, J = 7.1 Hz, OCH2CH3), 2.41 [1 H, m, (CH3)2CH], 1.38
[9 H, s, C(CH3)3], 1.34 (3 H, t, J = 7.1 Hz, OCH2CH3), 0.92 (3 H, d,
J = 6.7 Hz, CH3CHCH3), 0.83 (3 H, d, J = 6.7 Hz, CH3CHMe).
13C NMR (100 MHz, CDCl3): d = 173.3 (C), 161.4 (C), 155.5 (C),
147.4 (C), 126.8 (CH), 80.1 (C), 61.4 (CH2), 58.0 (CH), 33.3 (CH),
28.3 (CH3), 19.5 (CH3), 17.3 (CH3), 14.4 (CH3).
(S)-Ethyl 2-{1-[N-(tert-butoxycarbonyl)-2,2,2-trifluoroacetamido]-
2-methylpropyl}thiazole-4-carboxylate (700 mg, 1.65 mmol) was
dissolved in EtOH (16.5 mL) and EtONa (0.336 mg, 4.95 mmol, 3
equiv) was added. The solution was stirred at r.t. for 4 h then evap-
orated in vacuo. The residue was partitioned between EtOAc (20
mL) and H2O (20 mL) and the aqueous layer was further extracted
with EtOAc (2 × 10 mL). The combined organic extracts were dried
(Na2SO4) and evaporated in vacuo. Trituration of the residue with
PE afforded the product.
MS (APCI): m/z (%) = 329 (100) [M + H+].
Yield: 440 mg (81%); colourless solid; ee >98%.
(S)-Ethyl 2-[1-(tert-Butoxycarbonylamino)-2-methylpropyl]thi-
azole-4-carboxylate (7); Holzapfel Method4a
KHCO3 (0.176 g, 1.76 mmol, 8 equiv) was added to a solution of
(S)-tert-butyl 1-amino-3-methyl-1-thioxobutan-2-ylcarbamate (50
mg, 0.22 mmol) in DME (2 mL) and the mixture was stirred vigor-
ously for 5 min. Ethyl bromopyruvate (83 mL, 0.66 mmol, 3 equiv)
(S)-Ethyl 2-{1-[N-(tert-butoxycarbonyl)-2,2,2-trifluoroacet-
amido]-2-methylpropyl}thiazole-4-carboxylate (8); Nicolaou
Method7
NaHCO3 (868 mg, 10.33 mmol, 8 equiv) was added to a solution of
(S)-tert-butyl 1-amino-3-methyl-1-thioxobutan-2-ylcarbamate (300
Synthesis 2007, No. 22, 3535–3541 © Thieme Stuttgart · New York

3540
E. A. Merritt, M. C. Bagley
PAPER
mg, 1.29 mmol) in anhydrous DME (15 mL). Ethyl bromopyruvate
(0.49 mL, 755 mg, 3.87 mmol, 3 equiv) was added and the solution
was stirred at r.t. for 16 h. The mixture was evaporated in vacuo and
the residue was partitioned between H2O (30 mL) and Et2O (15
mL). The aqueous layer was further extracted with Et2O (15 mL)
and the combined organic extracts were washed with brine (15 mL),
dried (Na2SO4) and evaporated in vacuo. The residue was dissolved
in anhydrous DME (15 mL) and cooled to 0 °C. Pyridine (0.94 mL,
919 mg, 11.61 mmol, 9 equiv) was added slowly, followed by drop-
wise addition of TFAA (0.73 mL, 1.09 g, 5.16 mmol, 4 equiv), and
the solution was stirred at 0 °C for 2 h. Et3N (0.36 mL, 261 mg, 2.58
mmol, 2 equiv) was added and the reaction mixture was warmed to
r.t. and evaporated in vacuo. The residue was dissolved in CHCl3
(20 mL), washed with H2O (20 mL) and brine (10 mL), dried
(Na2SO4) and evaporated in vacuo. Purification of the residue by
column chromatography (PE–EtOAc, 3:1) afforded the title com-
pound.
Yield: 6.77 g (77%); colourless solid; mp 148–150 °C (CHCl3);
[a]D22 –45.4 (c 1.00, CHCl3).
HRMS: m/z [M + H+] calcd for C12H23N2O4: 259.1652; found:
259.1654.
IR (CH2Cl2): 3412, 3217, 2922, 1694, 1634, 1456, 1377, 1268,
1221, 1173, 1135, 1089, 987, 942, 861, 784 cm–1.
1H NMR (400 MHz, CDCl3): 6.60–5.80 (2 H, br s, exch. D2O, 2 ×
NH), 4.16 (1 H, app. br s, 5-H), 3.70 (1 H, app. br s, 4-H), 1.55 (3 H,
s, 2-Me), 1.52 (3 H, s, 2-Me), 1.39 [9 H, s, C(CH3)3], 1.33 (3 H, d,
J = 6.1 Hz, 5-Me).
13C NMR (100 MHz, CDCl3): d = 172.7 (C), 94.8 (C), 81.1 (C), 74.2
(CH), 67.4 (CH), 28.3 (CH3), 25.3 (CH3), 18.9 (CH3).
MS (APCI): m/z (%) = 259 (25) [M + H+], 221 (17), 204 (22), 203
(70), 159 (100), 145 (5).
(4R,5R)-tert-Butyl 4-Cyano-2,2,5-trimethyloxazolidine-3-car-
boxylate (11)
Yield: 467 mg (85%); yellow oil; ee 88% after conversion into (S)-
ethyl 2-[1-(tert-butoxycarbonylamino)-2-methylpropyl]thiazole-4-
carboxylate (7) by the method outlined above.
(4S,5R)-tert-Butyl 4-carbamoyl-2,2,5-trimethyloxazolidine-3-car-
boxylate (6.70 g, 25.9 mmol) was dissolved in pyridine (150 mL)
and the solution was cooled to 0 °C. Phosphorus oxychloride (6.04
mL, 9.94 g, 64.9 mmol, 2.5 equiv) was added and the solution was
stirred at 0 °C for 3 h. The mixture was poured over ice then diluted
with H2O (150 mL) and extracted with Et2O (3 × 100 mL). The
combined organic extracts were washed sequentially with HCl (2
M, 150 mL), H2O (3 × 150 mL) and brine (100 mL), dried (Na2SO4)
and evaporated in vacuo to afford the title compound.
(4S,5R)-3-(tert-Butoxycarbonyl)-2,2,5-trimethyloxazolidine-4-
carboxylic Acid (9)
N-Boc-L-threonine (7.50 g, 34.2 mmol) was dissolved in THF (200
mL) and 2,2-dimethoxypropane (42.07 mL, 35.64 g, 342.2 mmol,
10 equiv) and PPTS (2.58 g, 10.3 mmol, 0.3 equiv) was added. The
solution was heated at reflux for 16 h then allowed to cool and evap-
orated in vacuo. The residue was partitioned between EtOAc (200
mL) and H2O (200 mL), and the aqueous layer was further extracted
with EtOAc (2 × 100 mL). The combined organic extracts were
washed with brine (100 mL), dried (Na2SO4) and evaporated in vac-
uo to give the title compound.
22
Yield: 4.88 g (78%); colourless solid; mp 44–47 °C (CHCl3); [a]D
–69.4 (c 1.00, CHCL3).
HRMS: m/z [M + H+] calcd for C12H21N2O3: 241.1547; found:
241.1547 [M + H+].
22
Yield: 8.81 g (99%); off-white solid; mp 91–92 °C (CHCl3); [a]D
–60.0 (c 1.00, CHCl3).
IR (CH2Cl2): 3058, 2982, 2936, 2245, 1713, 1477, 1458, 1367,
1318, 1266, 1216, 1167, 1132, 1096, 993, 961, 936, 857, 776 cm–1.
1H NMR (400 MHz, CDCl3): 4.37 (1 H, m, 5-H), 4.04 (0.3 H, br d,
J = 6.1 Hz, 4-H), 3.96 (0.7 H, d, J = 7.3 Hz, 4-H), 1.61 (3 H, s, 2-
Me), 1.56 (3 H, s, 2-Me), 1.45 [9 H, s, C(CH3)3], 1.38 (3 H, d,
J = 6.1 Hz, 5-Me).
HRMS: m/z [M + H+] calcd for C12H22NO5: 260.1492; found:
260.1491.
IR (CH2Cl2): 3468, 3067, 2923, 1754, 1666, 1459, 1367, 1133, 988,
949, 856, 783, 722 cm–1.
13C NMR (100 MHz, CDCl3): d = 150.5 (C), 117.2 (C), 95.8 (C),
95.2 (C), 82.2 (C), 74.1 (CH), 73.9 (CH), 53.0 (CH), 30.3 (CH3),
29.7 (CH3), 28.3 (CH3), 27.8 (CH3), 26.5 (CH3), 25.4 (CH3), 24.5
(CH3), 18.3 (CH3).
1H NMR (400 MHz, CDCl3): d = 10.47 (1 H, br s, exch. D2O, OH),
4.16 (1 H, dq, J = 8.0, 6.0 Hz, 5-H), 3.93 (0.38 H, d, J = 8.0 Hz, 4-
H), 3.86 (0.62 H, d, J = 8.0 Hz, 4-H), 1.59 (1.86 H, s, 2-Me), 1.53
(1.14 H, s, 2-Me), 1.51 (1.86 H, s, 2-Me), 1.48 (1.14 H, s, 2-Me),
1.42 [3.43 H, s, C(CH3)3], 1.37 (3 H, d, J = 6.0 Hz, 5-Me), 1.34
[5.57 H, s, C(CH3)3].
13C NMR (100 MHz, CDCl3): = 171.2 (C), 175.8 (C), 152.3 (C),
150.9 (C), 95.3 (C), 94.7 (C), 81.4 (C), 80.8 (C), 73.9 (CH), 73.5
(CH), 66.0 (CH), 66.0 (CH), 28.3 (CH3), 28.2 (CH3), 27.7 (CH3),
26.5 (CH3), 24.8 (CH3), 23.9 (CH3), 18.9 (CH3).
+
MS (APCI): m/z (%) = 258 (100) [M + NH4 ], 241 (40) [M + H+],
202 (15), 114 (50).
(4S,5R)-tert-Butyl 4-Carbamothioyl-2,2,5-trimethyloxazoli-
dine-3-carboxylate (12)
(4R,5R)-tert-Butyl 4-cyano-2,2,5-trimethyloxazolidine-3-carboxy-
late (4.80 g, 20.0 mmol) was dissolved in MeOH (100 mL) and am-
monium sulfide (50 wt% in H2O, 5.44 mL, 40.0 mmol, 2 equiv) was
added. The solution was stirred at r.t. for 24 h then evaporated in
vacuo and the residue was partitioned between EtOAc (100 mL)
and H2O (100 mL). The aqueous layer was further extracted with
EtOAc (2 × 50 mL) and the combined organic extracts were dried
(Na2SO4) and evaporated in vacuo to yield the title compound.
MS (APCI): m/z (%) = 260 (5) [M + H+], 204 (45), 160 (100), 146
(32).
(4S,5R)-tert-Butyl 4-Carbamoyl-2,2,5-trimethyloxazolidine-3-
carboxylate (10)
To a stirred solution of (4S,5R)-3-(tert-butoxycarbonyl)-2,2,5-tri-
methyloxazolidine-4-carboxylic acid (8.80 g, 33.9 mmol) and Et3N
(4.97 mL, 3.61 g, 35.63 mmol, 1.05 equiv) in anhydrous THF (200
mL) at 0 °C was added ethyl chloroformate (3.41 mL, 3.87 g, 35.63
mmol, 1.05 equiv) and the mixture stirred for 1 h. Aqueous NH3
(35%, 100 mL) was added and the solution was allowed to warm to
r.t. and stirred for 24 h. The organic solvent was removed in vacuo
and the resulting aqueous solution was extracted with EtOAc
(3 × 100 mL). The combined organic extracts were washed sequen-
tially with H2O (100 mL) and brine (100 mL), dried (Na2SO4) and
evaporated in vacuo to yield the title compound.
Yield: 5.40 g (99%); pale-yellow solid; mp 106–108 °C (Et2O);
[a]D22 –8.2 (c 1.00, CHCl3) [Lit.7 –9.8 (c 0.19, CHCl3)].
HRMS: m/z [M + H+] calcd for C12H23N2O3S: 275.1424; found:
275.1424.
IR (CH2Cl2): 3307, 3196, 2925, 1672, 1619, 1443, 1368, 1265,
1139, 1090, 978, 940, 855, 736 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.86 (2 H, br s, exch. D2O, 2 ×
NH), 4.21 (1 H, d, J = 7.7 Hz, 5-H), 4.06 (1 H, br s, 4-H), 1.57 (6 H,
s, 2 × 2-CH3), 1.36 [12 H, app. s, C(CH3)3 and 5-CH3].
Synthesis 2007, No. 22, 3535–3541 © Thieme Stuttgart · New York

PAPER
Holzapfel–Meyers–Nicolaou Hantzsch Thiazole Synthesis
3541
13C NMR (100 MHz, CDCl3): d = 205.6 (C), 152.2 (C), 125.5 (CH),
94.8 (C), 81.6 (C), 73.9 (CH), 30.3 (CH3), 28.3 (CH3), 26.2 (CH3),
19.2 (CH3).
MS (ES+): m/z (%) = 297 (7) [M + Na+], 219 (12), 161 (100), 133
(27), 116 (40).
Acknowledgment
We thank the EPSRC and the Royal Society for funding, Robert L.
Jenkins for valuable technical assistance and the EPSRC Mass
Spectrometry Service at the University of Wales, Swansea UK for
mass spectra. We would also like to thank Dr Chris Mason and
CEM UK Ltd for technical assistance with low temperature micro-
wave irradiation experiments.
(4S,5R)-tert-Butyl 4-[4-(Ethoxycarbonyl)thiazol-2-yl]-2,2,5-tri-
methyloxazolidine-3-carboxylate (13)
NaHCO3 (13.23 g, 157.4 mmol, 8 equiv) was added to a solution of
(4S,5R)-tert-butyl 4-carbamothioyl-2,2,5-trimethyloxazolidine-3-
carboxylate (5.40 g, 19.7 mmol) in anhydrous DME (100 mL). Eth-
yl bromopyruvate (7.41 mL, 11.51 g, 59.0 mmol, 3 equiv) was add-
ed and the solution was stirred at r.t. for 16 h. The mixture was
evaporated in vacuo and the residue partitioned between H2O (200
mL) and Et2O (100 mL). The aqueous layer was further extracted
with Et2O (100 mL) and the combined organic extracts were washed
with brine (100 mL), dried (Na2SO4) and evaporated in vacuo. The
residue was dissolved in anhydrous DME (100 mL) and the solution
was cooled to 0 °C. Pyridine (14.32 mL, 14.01 g, 177.1 mmol, 9
equiv) was added slowly, followed by dropwise addition of TFAA
(11.13 mL, 16.56 g, 78.7 mmol, 4 equiv) and the solution was
stirred at 0 °C for 2 h. Et3N (5.49 mL, 3.98 g, 39.4 mmol, 2 equiv)
was added and the reaction mixture was warmed to r.t. and evapo-
rated in vacuo. The residue was dissolved in CHCl3 (200 mL),
washed with H2O (200 mL) and brine (100 mL), dried (Na2SO4) and
evaporated in vacuo. Purification of the residue by column chroma-
tography (PE–EtOAc, 3:1) afforded the title compound.
References
(1) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X. Chem.
Rev. 2005, 105, 685.
(2) McDonald, L. A.; Ireland, C. M. J. Nat. Prod. 1992, 55, 376.
(3) Todorova, A. K.; Jüttner, F.; Linden, A.; Plüss, T.; von
Philipsborn, W. J. Org. Chem. 1995, 60, 7891.
(4) (a) Bredenkamp, M. W.; Holzapfel, C. W.; van Zyl, W. J.
Synth. Commun. 1990, 20, 2235. (b) Aguilar, E.; Meyers, A.
I. Tetrahedron Lett. 1994, 35, 2473.
(5) (a) (+)-Nostocyclamide: Moody, C. J.; Bagley, M. C. J.
Chem. Soc., Perkin Trans. 1 1998, 601. (b) Promothiocin
A: Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody,
C. J. J. Am. Chem. Soc. 2000, 122, 3301. (c) Lissoclinum
cyclic peptide analogues: Bertram, A.; Blake, A. J.;
Gonzàlez-López de Turiso, F.; Hannam, J. S.; Jolliffe, K.
A.; Pattenden, G.; Skae, M. Tetrahedron 2003, 59, 6979.
(d) GE2270 A:Müller, H. M.; Delgado, O.; Bach, T. Angew.
Chem. Int. Ed. 2007, 46, 4771.
(6) Boden, C. D. J.; Pattenden, G.; Ye, T. Synlett 1995, 417.
(7) (a) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Lee, S. H.;
Nevalainen, M.; Bella, M.; Estrada, A. A.; Funke, C.; Zécri,
F. J.; Bulat, S. J. Am. Chem. Soc. 2005, 127, 11159.
(b) Nicolaou, K. C.; Zak, M.; Safina, B. S.; Estrada, A. A.;
Lee, S. H.; Nevalainen, M. J. Am. Chem. Soc. 2005, 127,
11176.
(8) Merritt, E. A.; Bagley, M. C. Synlett 2007, 6, 954.
(9) Concurrent heating and cooling has been shown to improve
the synthesis of compounds that are inherently thermally
unstable, see: (a) Strauss, C. R.; Trainor, R. W. Aust. J.
Chem. 1995, 48, 1665. (b) Roberts, B. A.; Strauss, C. R.
Acc. Chem. Res. 2005, 38, 653.
Yield: 5.37 g (74%); off-white solid; mp 97–100 °C (PE–EtOAc);
[a]D22 –59.6 (c 1.00, CHCl3) [Lit.7 –51.0 (c 0.33, CHCl3)].
HRMS: m/z [M + H+] calcd for C17H27N2O5S: 371.1635; found:
371.1633.
IR (CH2Cl2): 3400, 2982, 1720, 1699, 1476, 1369, 1302, 1261,
1240, 1214, 1136, 1096, 1020, 942, 784 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.09 (1 H, s, 5¢-H), 4.73 (1 H, br
d, J = 6.0 Hz, 4-H), 4.36 (2 H, q, J = 6.7 Hz, OCH2CH3), 4.09 (1 H,
br s, 5-H), 1.63 (6 H, s, 2 × 2-CH3), 1.36 (3 H, d, J = 6.0 Hz, 4-CH3),
1.33 (3 H, t, J = 6.7 Hz, OCH2CH3), 1.12 [9 H, br s, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 173.4 (C), 161.2 (C), 151.3 (C),
146.7 (C), 127.3 (CH), 95.3 (C), 80.7 (C), 77.9 (CH), 65.9 (CH),
61.5 (CH2), 28.1 (CH3), 26.5 (CH3), 25.9 (CH3), 17.9 (CH3), 14.4
(CH3).
(10) Our previous studies showed that concurrent heating and
cooling had a small but significant effect on pyrazole
synthesis, see: Bagley, M. C.; Lubinu, M. C.; Mason, C.
Synlett 2007, 704.
(11) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J.
Chem. Soc., Perkin Trans. 1 1998, 1, 591.
MS (ES+): m/z (%) = 393 (45) [M + Na+], 371 (20) [M + H+], 271
(100), 257 (75), 213 (52), 167 (30).
(12) Nakamura, Y.; Shin, C.-G.; Umemura, K.; Yoshimura, J.
Chem. Lett. 1992, 1005.
(13) Tavecchia, P.; Gentili, P.; Kurz, M.; Sottani, C.; Bonfichi,
R.; Selva, E.; Lociuro, S.; Restelli, E.; Ciabatti, R.
Tetrahedron 1995, 51, 4867.
Synthesis 2007, No. 22, 3535–3541 © Thieme Stuttgart · New York