Organolithium-mediated diversification of peptide thiazoles

Article abstract of DOI:10.1021/ol047660j

(Chemical Equation Presented) We report a one-step, racemization-free method for the diversification of peptide thiazoles via direct lithiation of the thiazole ring. The method is compatible with N-Boc, N-trityl, carboxylic ester, and carboxamide protecti

Full text of DOI:10.1021/ol047660j

ORGANIC
LETTERS
2005
Vol. 7, No. 2
299-301
Organolithium-Mediated Diversification
of Peptide Thiazoles
Shaojiang Deng and Jack Taunton*
Department of Cellular and Molecular Pharmacology, UniVersity of California,
San Francisco, 600 16th Street, San Francisco, California 94143
taunton@cmp.ucsf.edu
Received November 12, 2004
ABSTRACT
We report a one-step, racemization-free method for the diversification of peptide thiazoles via direct lithiation of the thiazole ring. The method
is compatible with N-Boc, N-trityl, carboxylic ester, and carboxamide protecting groups and has been used to directly functionalize the thiazole
ring of cyclopeptide natural products.
Peptide thiazoles are common substructures of macrocyclic
natural products1 that exhibit a range of biological activities,
including potent immunosuppression,2 inhibition of bacterial
protein synthesis,3 and actin filament stabilization.4 In
addition, macrocyclic peptides containing thiazoles have been
synthesized with the aim of creating conformationally
preorganized scaffolds, which can potentially interact with
large protein surfaces and thus disrupt protein-protein
interactions.5
lack C5 substituents.6 To increase the structural diversity of
macrocyclic peptide thiazoles, we sought a method that
would allow facile substitution at C5 of the thiazole ring.
Existing methods for the synthesis of 5-substituted dipeptide
thiazoles require 4-7 steps after incorporation of the C5
substituent.7 A more efficient route would place the C5
diversification step as late as possible, using fully assembled
peptide thiazoles.
We considered that direct lithiation of peptide thiazoles
would provide an efficient C5 diversification strategy.
Although C5 lithiation of 2,4-disubstituted thiazoles is
precedented,8 lithiation of peptide thiazoles has not been
reported previously. Here, we report the direct lithiation of
The common biosynthetic precursor of peptide thiazoles
is cysteine, the â-carbon of which becomes C5 of the thiazole
heterocycle (eq 1).1a Perhaps because of this biosynthetic
(4) Marquez, B. L.; Watts, K. S.; Yokochi, A.; Roberts, M. A.; Verdier-
Pinard, P.; Jimenez, J. I.; Hamel, E.; Scheuer, P. J.; Gerwick, W. H. J. Nat.
Prod. 2002, 65, 866.
(5) (a) Wipf, P.; Fritch, P. C.; Geib, S. J.; Sefler, A. M. J. Am. Chem.
Soc. 1998, 120, 4105. (b) Somogyi, L.; Haberhauer, G.; Rebek, J., Jr.
Tetrahedron 2001, 57, 1699. (c) Singh, Y.; Stoermer, M. J.; Lucke, A. J.;
Glenn, M. P.; Fairlie, D. P. Org. Lett. 2002, 4, 3367.
constraint, the majority of peptide thiazole natural products
(6) For examples of peptide thiazole natural products with 5-methyl and
5-methoxymethyl substituents, see: (a) Selva, E.; Beretta, G.; Montanini,
N.; Saddler, G. S.; Gastaldo, L.; Ferrari, P.; Lorenzetti, R.; Landini, P.;
Ripamonti, F.; Goldstein, B. P. J. Antibiot. 1991, 44, 693. (b) Shimanaka,
K.; Kinoshita, N.; Iinuma, H.; Hamada, M.; Takeuchi, T. J. Antibiot. 1994,
47, 668.
(7) (a) Gordon, T. D.; Singh, J.; Hansen, P. E.; Morgan, B. A.
Tetrahedron Lett. 1993, 34, 1901. (b) Buchanan, J. L.; Mani, U. N.; Plake,
H. R.; Holt, D. A. Tetrahedron Lett. 1999, 40, 3985. (c) Suzuki, T.;
Nagasaki, A.; Okumura, K.; Shin, C.-G. Heterocycles 2001, 55, 835. (d)
Nagasaki, A.; Adachi, Y.; Yonezawa, Y.; Shin, C.-G. Heterocycles 2003,
60, 321.
(1) For a review on biosynthesis, see: (a) Roy, R. S.; Gehring, A. M.;
Milne, J. C.; Belshaw, P. J.; Walsh, C. T. Nat. Prod. Rep. 1999, 16, 249.
For reviews on isolation, see: (b) Jin, Z. Nat. Prod. Rep. 2003, 20, 584
and references contained therein.
(2) Sasse, F.; Steinmetz, H.; Schupp, T.; Petersen, F.; Memmert, K.;
Hofmann, H.; Heusser, C.; Brinkmann, V.; Von Matt, P.; Hofle, G.;
Reichenbach, H. J. Antibiot. 2002, 55, 543.
(3) (a) Rodnina, M. V.; Savelsbergh, A.; Matassova, N. B.; Katunin, V.
I.; Semenkov, Y. P.; Wintermeyer, W. Proc. Natl. Acad. Sci. U.S.A. 1999,
96, 9586. (b) Cameron, D. M.; Thompson, J.; March, P. E.; Dahlberg, A.
E. J. Mol. Biol. 2002, 319, 27.
10.1021/ol047660j CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/17/2004

thiazole-containing peptides, including the cyclopeptide
natural products ceratospongamide and epiceratosponga-
mide.9 The resulting 5-lithiated thiazoles react rapidly with
a variety of electrophiles to provide substitution products in
high yields and without epimerization.
We optimized lithiation conditions using a thiazole dipep-
tide derived from L-proline, Boc-L-Pro-Thia-OMe (1) (Thia
) thiazole), an intermediate used in the total synthesis of
ceratospongamide.10 Treatment of 1 with 1.05 equiv of LDA
for 30 s at -78 °C, followed by reaction with iodine for 5
min, provided the desired 5-iodo adduct in 87% yield (Table
1, entry 1). The methyl ester and Boc groups were stable
lithiated 1 with bromine and tosyl chloride13 provided the
5-bromo and 5-chloro adducts, respectively, in excellent
yields (entries 2 and 3). Reaction of lithiated 1 with tin,
sulfur, and nitrogen-based electrophiles gave equally good
results (entries 4-6). We next tested the reactivity of lithiated
1 toward a broad range of carbonyl electrophiles, including
ethyl chloroformate, benzoyl chloride, DMF, benzaldehyde,
and acetone. These reactions provided the corresponding
ester, ketone, aldehyde, and alcohol adducts in good to
excellent yields (entries 7-11). In the reaction with benz-
aldehyde, a 1:1 mixture of carbinol diastereomers was
obtained. Alkylation of lithiated 1 succeeded with methyl
iodide (entry 12) yet failed with allyl bromide (recovered
starting material). This problem was solved by adding 0.1
equiv of CuCN‚2LiCl2;14 the allylated product was thus
obtained in 85% yield (entry 13).
Table 1. Diversification at Thiazole C5 in
Boc-L-Pro-Thia-OMe 1
To extend our method to dipeptide thiazoles containing
amino acids other than proline, we focused on the L-alanine-
based thiazole 2 (Table 2), available in 50% overall yield
Table 2. Diversification at Thiazole C5 in Tr-L-Ala-Thia-OMe
product
2
entry
electrophile
E )
yield (%)a
1
2
3
4
5
6
7
8
I2
Br2
TsCl
I
Br
Cl
SnBu3
SBn
NBocNHBoc
COOEt
COPh
87
80
82
97
72
43b
77
70
68
88c
81
68
85d
Bu3SnCl
BnS-SBn
BocNdNBoc
EtOCOCl
PhCOCl
DMF
PhCHO
acetone
Me-I
product
entry
electrophile
E )
yield (%)a
1
2
3
4
5
6
7
8
I2
TsCl
I
Cl
SnBu3
SBn
NBocNHBoc
COOEt
COPh
CHO
CH(OH)Ph
C(OH)Me2
73
69
67
96
61b
65
70
82
87c
72
82c
9
CHO
10
11
12
13
CH(OH)Ph
C(OH)Me2
Me
Bu3SnCl
BnS-SBn
BocNdNBoc
EtOCOCl
PhCOCl
DMF
BrCH2CHdCH2
CH2CHdCH2
a Isolated yield. ∼20% of 5-tBuO2C-thiazole formed. c 1:1 diastereomer
b
ratio at C5 R position. d 0.1 equiv of CuCN‚2LiCl2 used.
9
10
11
PhCHO
acetone
under these conditions.11 Importantly, there was no racem-
ization at the proline-derived chiral center, as determined
by a modified Marfey protocol (see Supporting Informa-
tion).12
Encouraged by this result, we explored the scope of this
reaction with various electrophiles (Table 1). Reaction of
12
13
14
Me-I
BrCH2CHdCH2
n-Bu-I
Me
87
CH2CHdCH2
Bu-n
80d
79e
a Isolated yield. ∼20% of 5-tBuO2C-thiazole formed. c 1:1 diastereomer
ratio at C5 R position. d 0.1 equiv of CuCN‚2LiCl2 used. e 5 equiv of HMPA
used. Tr ) trityl.
b
(8) Metzger, J. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 6, pp 235-
331.
(9) Tan, L. T.; Williamson, R. T.; Gerwick, W. H.; Watts, K. S.;
McGough, K.; Jacobs, R. J. Org. Chem. 2000, 65, 419.
(10) (a) Yokokawa, F.; Sameshima, H.; Shioiri, T. Synlett 2001, 986.
(b) Deng, S.; Taunton, J. J. Am. Chem. Soc. 2002, 124, 916. (c) Kutsumura,
N.; Sata, N. U.; Nishiyama, S. Bull. Chem. Soc. Jpn. 2002, 75, 847. (d)
Yokokawa, F.; Sameshima, H.; In, Y.; Minoura, K.; Ishida, T.; Shioiri, T.
Tetrahedron 2002, 58, 8127.
(11) Lithiated thiazole 1 is stable at -78 °C for up to 30 min, with ∼5%
self-acylation product and ∼10% other decomposition products; lithiated
thiazole 2 is stable at -78 °C for at least 30 min with less than 2% self-
acylation product. Both decompose rapidly at -40 °C.
(12) Fujii, K.; Ikai, Y.; Oka, H.; Suzuki, M.; Harada, K. Anal. Chem.
1997, 69, 5146.
from N-trityl L-alanine (five steps, no purification of
intermediates required). Despite the presence of a secondary
amine, deprotonation with only 1.05 equiv of LDA,11
followed by reaction with a variety of electrophiles, produced
the 5-substituted adducts in 61-96% yields, again without
(13) Brummond, K. M.; Gesenkerg, K. D. Tetrahedron Lett. 1999, 40,
2231.
(14) Abarbri, M.; Thibonnet, J.; Be´rillon, L.; Dehmel, F.; Rottla¨nder,
M.; Knochel, P. J. Org. Chem. 2000, 65, 4618.
300
Org. Lett., Vol. 7, No. 2, 2005

racemization. In addition to the electrophiles shown in Table
1, we treated 5-lithiated 2 with cyclohexen-2-one, which gave
the 1,2-adduct as a 1:1 mixture of diastereomers (entry 11).
The 1,4-adduct was not detected. Although methylation and
allylation proceeded uneventfully (entries 12 and 13), our
initial attempts to alkylate 2 with 1-iodobutane failed. This
problem was solved by the addition of 5 equiv of HMPA,
which furnished the n-butyl adduct in 79% yield (entry 14).
The 5-substituted dipeptide thiazoles shown in Tables 1 and
2 have orthogonally protected amines and carboxylic acids
and are thus suitable for incorporation into linear and cyclic
polypeptide structures.
recovered starting material. However, the 5-iodo adduct 4
was obtained in 94% yield when 3.0 equiv of LDA was used.
To extend the thiazole lithiation chemistry to more
complex systems, we turned to the cyclic peptide natural
products ceratospongamide 5 and epiceratospongamide 7.11b,d
It should be noted that Shioiri and colleagues, in their
correction of the originally proposed structure of 7, found
that the isoleucine R-stereocenter of 5 readily epimerized
under acidic conditions to give 7.11d Treatment of 5 or 7 with
4.2 equiv of LDA, followed by quenching with iodine,
afforded the 5-iodo thiazole adducts in 70% yield. In both
cases, we were unable to detect epimerization by HPLC or
NMR analysis.
In summary, we have developed a one-step, epimerization-
free method for appending diverse substituents to the
5-position of peptide thiazoles. The method is compatible
with Boc and trityl protecting groups at the NH2-terminus
and ester and carboxamide groups at the CO2H-terminus.
We anticipate that the 5-bromo and iodo adducts will find
application in Pd-catalyzed cross-coupling reactions, which
will allow the preparation of diverse 5-aryl and heteroaryl
peptide thiazoles. Thiazole lithiation occurred easily in the
context of cyclopeptide natural products, thus providing
access to structures that, to our knowledge, could not be
obtained biosynthetically.
Our interest in directly preparing 5-lithiated thiazoles in
the context of polypeptides prompted us to test the model
thiazole 4-carboxamide 3 (Figure 1). Lithiation of N-
Acknowledgment. We thank the Sandler Family Foun-
dation for generous financial support. Mass spectra were
acquired by the UCSF Mass Spectrometry Facility, which
is funded by grants from NIH NCRR (RR04112 and
RR01614). J.T. is a Searle Scholar and a fellow of the Alfred
P. Sloan Foundation.
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1.
isopropyl carboxamide 3 with 1.05 equiv of LDA, followed
by reaction with iodine for 5 min at -78 °C, provided only
OL047660J
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