Improved procedure for the synthesis of thiazolium-type peptide coupling reagents: BMTB as a new efficient reagent

Article abstract of DOI:10.1016/S0040-4039(03)00928-6

An efficient scalable synthesis of 2-halothiazolium-type peptide coupling reagents has been developed. The key step is the formation of the 2-bromothiazole scaffold through cyclization of α-thiocyanato ketones with hydrogen bromide. Using this method, the new coupling reagent 2-bromo-N-methylthiazolium bromide (BMTB) was synthesized. BMTB was tested in a difficult model coupling reaction of two sterically hindered N-methylated amino acids and showed higher activity than the well-established peptide coupling reagent HATU.

Full text of DOI:10.1016/S0040-4039(03)00928-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4393–4394
Improved procedure for the synthesis of thiazolium-type peptide
ꢀ
coupling reagents: BMTB as a new efficient reagent
a,
b
c
c
c
c
Ralf Wischnat, * Joachim Rudolph, Roman Hanke, Roger Kaese, Achim May, Heidi Theis and
c
Undine Zuther
a
Bayer AG, Pharma Operations PH-OP-WP, Friedrich Ebert Str. 217, D-42096, Germany
b
Department of Chemistry Research, Bayer Corporation, Pharmaceutical Division, 400 Morgan Lane, West Haven, CT 06516,
USA
c
Bayer AG, Central Research, Building Q18, D-51368 Leverkusen, Germany
Received 28 January 2003; revised 8 April 2003; accepted 8 April 2003
Abstract—An efficient scalable synthesis of 2-halothiazolium-type peptide coupling reagents has been developed. The key step is
the formation of the 2-bromothiazole scaffold through cyclization of a-thiocyanato ketones with hydrogen bromide. Using this
method, the new coupling reagent 2-bromo-N-methylthiazolium bromide (BMTB) was synthesized. BMTB was tested in a difficult
model coupling reaction of two sterically hindered N-methylated amino acids and showed higher activity than the well-established
peptide coupling reagent HATU. © 2003 Elsevier Science Ltd. All rights reserved.
The coupling of sterically hindered N-alkylated amino
stration for the potency of these reagents, the authors
published the first chemical synthesis of the copiously
N-methylated cyclic undecapeptide cyclosporin O.
acids is a challenge in peptide chemistry for which a
1
8
satisfactory solution has not been found. Use of a
conventional peptide coupling reagent in such cases
often results in poor yields that are frequently associ-
ated with racemization. The finding that HOAt-based
coupling reagents such as HATU are superior to
HOBt-type reagents represented an important improve-
ment. However, these reagents do not provide a general
Due to our interest in the synthesis of peptides consist-
ing of multiple N-alkylated amino acids, we were in
need of BEMT which has not been commercially avail-
able to date. According to the previously described
procedure, BEMT is synthesized starting from thiourea
5a
2
,3
solution for difficult coupling reactions. In addition,
HOAt is expensive, and safety concerns with this
3
which is converted to the aminothiazole 4. Com-
pound 4 is then transformed into the corresponding
bromothiazole 5 which is subsequently N-ethylated
using Meerwein reagent. In our efforts to repeat the
4
reagent have recently been raised. In the past years,
considerable efforts to find new improved coupling
reagents and procedures have been observed in the
6
described synthesis, we encountered difficulties in the
transformation of the aminothiazole into the corre-
sponding bromothiazole 5, namely the formation of
considerable amounts of dibrominated compound 6 as
side product (Scheme 1). Our attempts to improve the
selectivity of this step were unsuccessful. In addition,
purification of 5 via distillation proved to be difficult
and not suitable for large-scale application.
5
literature.
One of these efforts yielded the new peptide coupling
reagent 2-bromo-3-ethyl-4-methyl thiazolium tetra-
fluoroborate (BEMT, 1a) which was introduced by Xu
in 1999. Together with the coupling reagent 2-bromo-1-
ethyl pyridinium tetrafluoroborate (BEP, 2), BEMT is
described to work well for sterically hindered amino
acid peptide couplings, particularly for the case of
6,7
N-alkylated amino acids. As an experimental demon-
ꢀ
Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)00928-6
*
Corresponding author. Tel.: +49 (0) 202-36-7691; fax: +49 (0)
02-36-7663; e-mail: ralf.wischnat.rw@bayer-ag.de
6
2
Scheme 1. Synthesis of BEMT following a protocol by Xu.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00928-6

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394
R. Wischnat et al. / Tetrahedron Letters 44 (2003) 4393–4394
We therefore needed a new strategy to access the key
compound 5.
Starting from commercially available chloroacetone or
other a-chloroketones, thiocyanatopropan-2-one 7 was
9
synthesized following the procedure by Hantzsch. We
found that treatment of 7 with HBr in dichloromethane
resulted, after neutralization, in quantitative formation
1
0
of the free thiazole 5. Distillation provided the pure
final product in >80% yield. Finally, alkylation using
Meerwein salt gave the desired product BEMT 1a. With
this efficient process in hand, BEMT was synthesized on
a 0.5 kg scale. However, the use of Meerwein salt is not
recommended for large-scale applications due to safety
and environmental concerns. In our efforts to identify a
less expensive and less toxic alkylating source which
would lead to an equally potent coupling reagent, we
employed methylbromide which furnished the thiazolium
Figure 1. Conversion for the reaction shown in Scheme 3 using
the coupling reagents 1a, 1b, and 2.
In none of the model reactions investigated so far we
1
1
found any significant levels of racemization, and cou-
salt 1b (Scheme 2).
1
2
pling additives such as HOBt are therefore unnecessary.
Overall, we recommend BMTB as an attractive alterna-
To evaluate the coupling activity of these reagents we
performed a comparison study. 1 Equiv. of the amino
acid N-Boc-MeIle was coupled with 1 equiv. of MeIle-
OBn using 1.5 equiv. of reagent 1a, 1b and 2, respectively
13
tive for known peptide coupling reagents. BMTB is
crystalline and non-hygroscopic, easy to handle and
stable at room temperature for months. The scope of this
and similar reagents for other condensation reactions is
currently being investigated in our laboratories.
(
Scheme 3). This reaction is known to proceed very
poorly using classical coupling reagents, since the N-
methyl groups as well as bulky side chains contribute to
substantial steric hindrance.
Supplementary material
The following supplementary material is available on-
line: experimental procedure for the coupling experi-
ments; general procedure for the synthesis of
As shown in Figure 1, all three reagents 1a, 1b, and 2 were
superior to PyBop or the combination EDC/HOBt which
both failed to show any activity in this case. More
2
-halo-1,3-thiazoles; general procedure for the N-alkyla-
importantly, the new reagent 1b (2-b
6 romo-3-m6 ethyl-4-
tion of 2-halo-1,3-thiazoles; analytical data for the
reagent BMTB.
methyl thiazolium bromide, BMTB) demonstrated
6
6
higher conversion rates than the powerful coupling
reagent HATU.
References
1. Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243–2266.
2
3
. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397–4398.
. Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F.
J. Chem. Soc., Chem. Commun. 1994, 201–203.
4
5
. http://www.ovpr.uga.edu/bio/hoatsafety.html.
. See for example: (a) Thern, B.; Rudolph, J.; Jung, G. Angew.
Chem., Int. Ed. 2002, 41, 2307–2309; (b) DalPazzo, A.;
Bergonzi, R.; Ni, M. Tetrahedron Lett. 2001, 42, 3925–3927.
. Li, P.; Xu, J. C. Tetrahedron Lett. 1999, 40, 8301–8304.
. Li, P.; Xu, J. C. Chem. Lett. 2000, 204–205.
Scheme 2. New general synthesis of thiazolium type peptide
coupling reagents. (i) NaSCN, EtOH; (ii) HBr, CH Cl ; (iii)
2
2
alkylating reagent.
6
7
8
9
. Li, P.; Xu, J. C. J. Org. Chem. 2000, 65, 2951–2958.
. (a) Hantzsch, K. Chem. Ber. 1927, 60, 2541–2544; (b) ibid.
1928, 61, 1776–1788.
1
0. This method has previously been described for the synthesis
of chlorothiazoles. See for example: Gruenert, C.; Wichert,
K. Z. Chem. 1970, 10, 396–397.
1
1
1. Rudolph, J.; Wischnat, R. EP 1216997 A2, Bayer AG.
2. Racemization studies are described in a pending patent
application: Wischnat, R.; Rudolph, J., Bayer AG.
3. For the purchase of BMTB, please contact Johannes
Heckmann, Bayer AG, Chemicals Division, Marketing,
Building B106, D-51368 Leverkusen, Germany. Tel.: +49-
214-30-33095; fax: +49-214-3025336. E-mail: johannes.
heckmann.jh@bayer-ag.de.
1
Scheme 3. Model reaction for the comparison of the peptide
coupling reagents 1a, 1b, and 2. Reaction conditions: 1 equiv.
of each amino acid, 2 equiv. DIPEA, 1.5 equiv. reagent,
CH Cl , rt, 2 h.
2
2