Regio- and Stereoselective Synthesis of α-Chiral 2-Substituted 4-Bromothiazoles from 2,4-Dibromothiazole by Bromine-Magnesium Exchange. Building Blocks for the Synthesis of Thiazolyl Peptides and Dolabellin

Article abstract of DOI:10.1055/s-2003-43361

Fragment 6 of thiazolyl peptide GE 2270 D2 and fragment 11 of dolabellin were synthesized stereoselectively from 2,4-dibromothiazole (1) in three (6, 44% overall yield) and five synthetic steps (11, 63% overall yield). Key to the success of the strategy w

Full text of DOI:10.1055/s-2003-43361

LETTER
131
Regio- and Stereoselective Synthesis of a-Chiral 2-Substituted 4-Bromo-
thiazoles from 2,4-Dibromothiazole by Bromine–Magnesium Exchange.
Building Blocks for the Synthesis of Thiazolyl Peptides and Dolabellin
4
-Bromothiazol-2-
l
yl Ma
g
e
nesium Bro
x
mide andra Spieß, Golo Heckmann, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 9 September 2003
imines can be reduced directly to amines or they can be
hydrolyzed to the corresponding ketones, which are fur-
ther reduced to alcohols. Since aryl lithium compounds
have been reported to undergo double addition to activat-
Abstract: Fragment 6 of thiazolyl peptide GE 2270 D2 and frag-
ment 11 of dolabellin were synthesized stereoselectively from 2,4-
dibromothiazole (1) in three (6, 44% overall yield) and five synthet-
ic steps (11, 63% overall yield). Key to the success of the strategy
was a bromine-magnesium exchange, which proceeds with excel- ed nitriles7 and since 2-thiazolyl lithium reagents proved
to be unstable at Q≥0 °C we did not employ the known8
lent regio- and chemoselectivity at carbon atom C-2 of 1.
regioselective bromine–lithium exchange 1 → 2
Key words: asymmetric synthesis, magnesium, metalations, natu-
ral products, thiazoles
(Scheme 2) to prepare a 2-metalated 4-bromothiazole. In-
stead, we attempted a regioselective bromine–magnesium
exchange according to the protocol by Knochel et al.9 It
turned out that this reaction works well and with perfect
regioselectivity to give the desired magnesium reagent 3.
We found the latter compound to be stable even at ambi-
ent temperature. It reacted nicely with nitriles at 0 °C to
form a single addition product.
2,4-Disubstituted thiazoles are important subunits in a
number of structurally varied natural products.1 Besides
the classic Hantzsch synthesis2 several new methods for
their preparation have been devised in recent years.3 Re-
search in our group has focussed on easily accessible 2,4-
dibromothiazole4 (1, Scheme 1) as a versatile building
block, which can be used in sequential regioselective
cross-coupling reactions.5 Unfortunately, this approach
has so far not been applicable6 to the construction of 4-
bromothiazoles B, which bear a stereogenic center at the
a-carbon atom of the 2-substituent and are potential
precursors for the synthesis of chiral thiazoles A.
i-PrMgBr
n-BuLi
or s-BuMgCl
Br
Br
−78 °C (Et2O)
0 °C (THF)
N
N
1
Li
MgX
2
ref.8a
2
this work
S
S
2
3
Scheme 2 Bromine–metal exchange of compound 1 under
different conditions leading to lithium compound 2 and magnesium
compound 3
R1
Br
Br
4
N
N
N
R
R
*
*
Br
S
S
S
2
In a first application, we used intermediate 3 to prepare
X
X
the enantiomerically pure bithiazole fragment
6
A
X =OH, NH2
B
1
(Scheme 3) related to the thiazolyl peptides GE 2270.10
The relative configuration of the 1,2-amino alcohol has
been presumed to be threo.11
Scheme 1 Retrosynthetic strategy for the preparation of 2,4-disub-
stituted thiazoles with a stereogenic center at the a-carbon atom of the
2-substituent
1. i-PrMgBr, 0 °C
As a potential alternative approach to compounds B we
envisaged an umpolung at carbon atom C-2 of compound
1 via bromine–metal exchange followed by an electro-
philic quench. In this communication, we report the appli-
cation of this strategy to the synthesis of two natural
product fragments.
Ph
NaBH4
2.
Boc2O, r.t.
(CH2Cl2)
Br
−78 °C → r.t.
(EtOH/THF)
NC OTBS
0 °C (THF)
N
1
94%
OTBS
S
62% overall
NH2
4
1. ZnCl2, t-BuLi
−78 °C (THF)
2. 1, r.t. (THF)
In order to access both amines of type A (X = NH2) and
alcohols of type A (X = OH) we planned to treat a 2-met-
alated 4-bromothiazole with nitriles. The intermediate
Br
N
S
Br
2'
[PdCl2(PPh3)2]
N
N
75%
OTBS
NHBoc
S
OTBS
S
NHBoc
SYNLETT 2004, No. 1, pp 0131–0133
0
5.
0
1.
2
0
0
4
5
6
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43361; Art ID: G23503ST.pdf
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Stereoselective synthesis of the thiazolyl peptide frag-
ment 6 by nitrile addition/reduction and subsequent cross-coupling

132
A. Spieß et al.
LETTER
Following the approach described above, magnesium change and trapped with carbon dioxide. Immediate me-
compound 3 was generated and treated with enantiomeri- thylation of the free acid yielded compound 10, which was
cally pure tert-butyldimethylsilyl- (TBS-) protected (R)- deprotected to the desired enantiomerically pure alcohol
mandelonitrile12 to yield an intermediate imine, which 11.19
was directly reduced with NaBH4 in EtOH/THF.13,14 The
reduction proceeded under Felkin–Anh control and the
In summary, we have described a new route to a-chiral 2-
substituted 4-bromothiazoles, which can be further used
major product (dr = 79:21) was proven to be the desired
for the synthesis of naturally occurring 2,4-disubstituted
O-TBS-protected threo-amino alcohol 4.15 The total yield
thiazole fragments. Due to its brevity and due to the high
stereoselectivities, which can be achieved, the method ap-
of the sequence nitrile addition/reduction was 73% and
the desired compound was isolated in 62% yield after sep-
pears to be superior to known procedures. Further synthet-
aration from the minor erythro-product (11% yield). Sub-
ic work directed towards the synthesis of a-chiral 2,4-
disubstituted thiazoles is in progress and will be reported
in due course.
sequent N-tert-butyloxycarbonyl- (Boc-) protection of the
free amino group yielded 4-bromothiazole 5, which was
converted by bromine-metal exchange into the corre-
sponding zinc compound.5c Regioselective Negishi cross-
Acknowledgment
coupling with another equivalent of 2,4-dibromothiazole
proceeded as expected5 and generated the desired bithiaz-
ole 6.
This project was supported by the Fonds der Chemischen Industrie.
The donation of chemicals by OMG AG (Hanau-Wolfgang) and by
Wacker-Chemie (München) is gratefully acknowledged.
The nitrile addition/reduction sequence can also be con-
ducted enantioselectively. This was demonstrated in the
synthesis of the a-chiral alcohol 11 whose enantiomer is
found as a fragment in the cytotoxic bisthiazole metabo-
lite dolabellin16 (Scheme 4). The high yield achieved in
the formation of ketone 7 underlines the excellent nucleo-
philicity of magnesium compound 3. Alternative ap-
proaches gave lower chemical yields.8 The enantio-
selective ketone reduction was best conducted using
Corey’s procedure,17 which delivered the desired alcohol
818 in excellent yield.
References
(1) General reviews on thiazoles: (a) Kikelj, D.; Urleb, U. In
Science of Synthesis, Houben–Weyl Methods of Molecular
Transformations, Vol. 11; Schaumann, E., Ed.; Thieme:
Stuttgart, 2002, 627. (b) Liebscher, J. In Houben–Weyl
Methoden der Organischen Chemie, 4th Ed., Vol. E 8b;
Schaumann, E., Ed.; Thieme: Stuttgart, 1994, 1.
(c) Dondoni, A.; Merino, P. In Comprehensive Heterocyclic
Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V.; Bird, C. W., Eds.; Pergamon: Oxford, 1996, 373.
(d) Metzger, J. V. In Comprehensive Heterocyclic
Chemistry, Vol. 6; Katritzky, A. R.; Rees, C. W.; Bird, C.
W.; Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984,
235.
After triethylsilyl- (TES-) protection of the free alcohol
the 4-lithium thiazole was formed by bromine–lithium ex-
(2) Selected examples: (a) Buchanan, J. L.; Bohacek, R. S.;
Luke, G. P.; Hatada, M.; Lu, X.; Dalgarno, D. C.; Narula, S.
S.; Yuan, R.; Holt, D. A. Bioorg. Med. Chem. Lett. 1999, 9,
2353. (b) Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.;
Moody, C. J. J. Am. Chem. Soc. 2000, 122, 3301. (c) Xia,
Z.; Smith, C. D. J. Org. Chem. 2001, 66, 3459. (d) Lee, C.
B.; Wu, Z.; Zhang, F.; Chappell, M. D.; Stachel, S. J.; Chou,
T.-C.; Guan, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2001,
123, 5249. (e) Cetusic, J. R. P.; Green, F. R. III; Graupner,
P. R.; Oliver, M. P. Org. Lett. 2002, 4, 1307.
(3) Selected examples: (a) Wipf, P.; Venkatraman, S. J. Org.
Chem. 1996, 61, 8004. (b) Heck, S.; Dömling, A. Synlett
2000, 424. (c) Boden, C. D. J.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 2000, 875. (d) Frontrodona, X.; Diaz, S.;
Linden, A.; Villalgordo, J. M. Synthesis 2001, 2021.
(e) Sugiyama, H.; Yokokawa, F.; Shioiri, T. Tetrahedron
2003, 59, 6579.
BH3, 0 °C (THF)
1. s-BuMgCl, 0 °C
Ph
Ph
2.
Br
Br
O
B
NC
N
N
N
0 °C (THF)
1
S
S
83%
97%
95% ee
O
OH
7
8
1. t-BuLi, −78 °C (Et2O)
2. CO2, −78 °C → r.t. (Et2O)
Br
TESCl, imidazole
r.t. (DMF)
N
3. MeI, K2CO3, r.t. (DMF)
S
98%
80%
OTES
9
MeOOC
N
MeOOC
TBAF
N
(4) Reynaud, P.; Robba, M.; Moreau, R. C. Bull. Soc. Chim. Fr.
1962, 1735.
r.t. (THF)
S
S
quant.
(5) (a) Bach, T.; Heuser, S. Tetrahedron Lett. 2000, 41, 1707.
(b) Bach, T.; Heuser, S. Angew. Chem. Int. Ed. 2001, 40,
3184. (c) Bach, T.; Heuser, S. J. Org. Chem. 2002, 67, 5789.
(d) Bach, T.; Heuser, S. Chem.–Eur. J. 2002, 8, 5585.
(e) Bach, T.; Heuser, S. Synlett 2002, 2089.
OH
OTES
10
11
Scheme 4 Enantioselective synthesis of the dolabellin fragment 11
by nitrile addition/reduction and subsequent carboxylation
(6) Spieß, A. PhD Thesis; Technical University: Munich, 2003.
(7) (a) Amouroux, R.; Axiotis, G. P. Synthesis 1981, 270.
(b) Chastrette, M.; Axiotis, G. P. Synthesis 1980, 889.
Synlett 2004, No. 1, 131–133 © Thieme Stuttgart · New York

LETTER
4-Bromothiazol-2-yl Magnesium Bromide
133
(8) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1988, 53, 1748. (b) Kelly, T. R.;
Jagoe, C. T.; Gu, Z. Tetrahedron Lett. 1991, 32, 4263.
(c) Nickson, T. E. J. Fluorine Chem. 1991, 55, 173.
(d) Nicolaou, K. C.; He, Y.; Roschangar, F.; King, N. P.;
Vourloumis, D.; Li, T. Angew. Chem. Int. Ed. 1998, 37, 84.
(e) Ung, A. T.; Pyne, S. G. Tetrahedron: Asymmetry 1998,
9, 1395.
0.82 (s, 9 H), 2.02 (br s, 2 H), 4.41 (d, 3J = 5.9 Hz, 1 H), 5.04
(d, 3J = 5.9 Hz, 1 H), 7.09 (s, 1 H), 7.19–7.26 (m, 5 H).
13C NMR (90 MHz, CDCl3): d = –5.3, –4.8, 18.0, 25.7, 60.6,
78.2, 117.0, 124.3, 127.0, 128.0, 128.1, 140.1, 173.9. Anal.
Calcd for C17H25BrN2OSSi (413.45): C, 49.39; H, 6.09; N,
6.78. Found: C, 49.45; H, 6.11; N, 6.71. The erythro-
diastereoisomer (0.47g, 1.13 mmol, 11%) was obtained as a
yellow liquid.
(9) Abarbri, A.; Thibonnet, J.; Berillon, L.; Dehmell, F.;
Rottländer, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618.
(10) Selva, E.; Ferrari, P.; Kurz, M.; Tavecchia, P.; Colombo, L.;
Stelle, S.; Restelli, E.; Goldstein, B. P.; Ripamonti, F.;
Denaro, M. J. Antibiot. 1995, 48, 1039.
(11) (a) Okumura, K.; Saito, H.; Shin, C.; Umemura, K.;
Yoshimura, J. Bull. Chem. Soc. Jpn. 1998, 71, 1863.
(b) Okumura, K.; Suzuki, T.; Shin, C. Heterocycles 2000,
53, 765.
(15) The relative configuration was proven by converting the
aminoalcohol 4 and its erythro-diastereoisomer into the
corresponding cyclic N-Boc protected N,O-acetals which
were studied independently by 1H NMR spectroscopy. In
addition, a known acetal11 was prepared by carboxylation of
product 5 at carbon atom C-4 (t-BuLi, CO2 in Et2O),
transformation into the corresponding ester (EtI in DMF),
TBS-deprotection (TBAF in THF) and acetal formation
(2,2-dimethoxypropane, TsOH in CH2Cl2). The
(12) Brussee, J.; Loos, W. T.; Kruse, C. G.; van der Gen, A.
Tetrahedron 1990, 46, 979.
(13) Brussee, J.; Dofferhoff, F.; Kruse, C. G.; van der G en, A.
Tetrahedron 1990, 46, 1653.
enantiomeric excess (95% ee) was determined by HPLC
analysis of the N-Boc protected product 5 (column:
Machery-Nagel, Nucleodex b-OH, 200 × 4.00 mm; eluent:
H2O/MeCN 20:80→0:100 over 30 min; flow rate: 1.0 mL/
min).
(14) Procedure for the Conversion 1→4: At 0 °C, 6.60 mL
(12.0 mmol) of a 1.80 M i-PrMgBr solution in Et2O was
added dropwise to a solution of 2.92 g (12.0 mmol) 2,4-
dibromothiazole in 30 mL of THF and the solution was
stirred for 15 min at 0 °C. Neat TBS-protected mandelo-
nitrile12 (2.47 g, 10.0 mmol) was added dropwise. The
mixture was stirred for 30 min at 0 °C and for another 30 min
at r.t. After adding 10 mL of EtOH the reaction mixture was
cooled to –78 °C and NaBH4 (0.76 g, 20.0 mmol) was added
carefully in small portions. The mixture was stirred for 2 h at
–78 °C and – after removing the cooling bath – over night at
r.t. The reaction mixture was quenched with 25 mL of sat. aq
NH4Cl solution and diluted with 200 mL Et2O. The organic
layer was washed with 200 mL H2O and 100 mL brine and
it was subsequently dried over Na2SO4. GC analysis
indicated a facial diastereoselectivity of 79:21. After
filtration the solvent was removed and the residue was
purified by flash chromatography (pentane/Et2O:
75:25→50:50). Compound 4 (2.55 g, 6.18 mmol, 62%) was
obtained as a yellow liquid. [a]D20 –47.9 (c 1.5, CHCl3). 1H
NMR (360 MHz, CDCl3): d = –0.21 (s, 3 H), –0.06 (s, 3 H),
(16) Sone, H.; Kondo, T.; Kiryu, M.; Ishiwata, H.; Ojika, M.;
Yamada, K. J. Org. Chem. 1995, 60, 4774.
(17) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988,
53, 2861.
(18) Analytical data of compound 8: [a]D20 +27.5 (c 0.80,
CHCl3). 1H NMR (360 MHz, CDCl3): d = 0.92 (d, 3J = 6.8
Hz, 3 H), 1.02 (d, 3J = 6.8 Hz, 3 H), 2.14–2.30 (m, 1 H), 2.60
(br s, 1 H), 4.80 (d, 3J = 4.8 Hz, 1 H), 7.19 (s, 1 H). 13C NMR
(90 MHz, CDCl3): d = 16.2, 18.8, 34.9, 76.4, 116.7, 124.3,
175.6. Anal. Calcd for C7H10BrNOS (236.13): C, 35.61; H,
4.27; N, 5.93. Found: C, 35.81; H, 4.38; N, 5.87.
(19) Analytical data of compound 11: [a]D20 +26.9 (c 1.15,
CHCl3). 1H NMR (360 MHz, CDCl3): d = 0.93 (d, 3J = 6.6
Hz, 3 H), 1.03 (d, 3J = 7.0 Hz, 3 H), 2.08 (br s, 1 H), 2.20–
2.35 (m, 1 H), 3.94 (s, 3 H), 4.82 (d, 3J = 4.8 Hz, 1 H), 8.16
(s, 1 H). 13C NMR (90 MHz, CDCl3): d = 16.2, 18.9, 35.0,
52.4, 76.7, 127.6, 146.4, 161.9, 175.7. Anal. Calcd for
C9H13NO3S (215.27): C, 50.21; H, 6.09; N, 6.51. Found: C,
49.91; H, 6.20; N, 6.29.
Synlett 2004, No. 1, 131–133 © Thieme Stuttgart · New York