Titanium(IV)-mediated tandem deprotection-cyclodehydration of protected cysteine N-amides: Biomimetic syntheses of thiazoline- and thiazole-containing heterocycles

Article abstract of DOI:10.1021/ol000178q

(matrix presented) The scope and limitations of TiCl₄-mediated Δ²-thiazoline synthesis via tandem deprotection-dehydrocyclization of trityl-protected cysteine N-amides is presented. While chemical yields are acceptable (53-96%), the

Full text of DOI:10.1021/ol000178q

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3289-3292
Titanium(IV)-Mediated Tandem
Deprotection−Cyclodehydration of
Protected Cysteine N-Amides:
Biomimetic Syntheses of Thiazoline-
and Thiazole-Containing Heterocycles
Prakash Raman,† Hossein Razavi,† and Jeffery W. Kelly*
Department of Chemistry and The Skaggs Institute of Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road (MB12),
La Jolla, California 92037
jkelly@scripps.edu
Received July 6, 2000
ABSTRACT
The scope and limitations of TiCl4-mediated ∆2-thiazoline synthesis via tandem deprotection−dehydrocyclization of trityl-protected cysteine
N-amides is presented. While chemical yields are acceptable (53−96%), the stereochemical outcomes vary on the basis of structural considerations
and reaction conditions (22−99% ee). Racemization at the C(2)-exomethine position limits the utility of this method for the formation of a
thiazoline within a peptide. Treatment of a tritylated Cys-Cys dipeptide with TiCl4 afforded the corresponding thiazole−thiazoline heterocycle
12 (38% yield, 97% ee).
Thiazoline and thiazole rings are structural motifs found in
numerous natural products.1 Their wide range of antitumor,
antiviral, and antibiotic activities, as well as their ability to
bind to proteins, DNA, and RNA, has fueled numerous
synthetic and biological investigations.2 The biosynthesis of
thiazolines appears to involve an attack by the cysteine’s
sulfur on the enzyme-activated amide carbonyl group of the
preceding residue.3 While dehydration of the resulting
tetrahedral intermediate affords a thiazoline ring, further
oxidation is required to give the corresponding thiazole.
(2) (a) McGowan, D. A.; Jordis, U.; Minster, D. K.; Hecht, S. M. J. Am.
Chem. Soc. 1977, 99, 8078-8079. (b) Minster, D. K.; Jordis, U.; Evans,
D. L.; Hecht, S. M. J. Org. Chem. 1978, 43, 1624-1626. (c) Walker, M.
A.; Heathcock, C. H. J. Org. Chem. 1992, 57, 5566-5568. (d) Fukuyama,
T.; Xu, L. J. Am. Chem. Soc. 1993, 115, 8449-8450. (e) Pattenden, G.;
Thom, S. M. J. Chem. Soc., Perkin Trans. 1 1993, 1629-1636. (f) Parsons,
R. L.; Heathcock, C. H. Tetrahedron Lett. 1994, 35, 1379-1382. (g)
Parsons, R. L. J.; Heathcock, C. H. Tetrahedron Lett. 1994, 35, 1383-
1384. (h) For a review see: Wipf, P. Chem. ReV. 1995, 95, 2115-2134. (i)
Parsons, R. L. J.; Heathcock, C. H. Synlett 1996, 1168-1170. (j) Wipf, P.;
Xu, W. J. Org. Chem. 1996, 61, 6556-6562. (k) Wipf, P.; Venkatraman,
S. Synlett 1997, 1-10. (l) Kuriyama, N.; Akaji, K.; Kiso, Y. Tetrahedron
1997, 53, 8323-8334. (m) White, J. D.; Kim, T.-S.; Nambu, M. J. Am.
Chem. Soc. 1997, 119, 103-111. (n) Ino, A.; Hasegawa, Y.; Murabayashi,
A. Tetrahedron Lett. 1998, 39, 3509-3512. (o) Akaji, K.; Kiso, Y.
Tetrahedron 1999, 55, 10685-10694.
† P.R. and H.R. contributed equally to this work.
(1) (a) Carmeli, S.; Moore, R. E.; Patterson, G. M. L.; Corbett, T. H.;
Valeriote, F. A. J. Am. Chem. Soc. 1990, 112, 8195. (b) Carmeli, S.; Moore,
R. E.; Patterson, G. M. L. Tetrahedron Lett. 1991, 32, 2593. (c)Jansen, R.;
Kunze, B.; Reichenbach, H.; Jurkiewicz, E.; Hunsmann, G.; Hofle, G.
Liebigs Ann. Chem. 1992, 357. (d) Kolter, R.; Moreno, F. Annu. ReV.
Microbiol. 1992, 46, 141-163. (e) Bayer, A.; Freund, S.; Nicholson, G.;
Jung, G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1336. (f) Yorgey, P.; Lee,
J.; Koerdel, J.; Vivas, E.; Warner, P.; Jebaratnam, D.; Kolter, R. Proc. Natl.
Acad. Sci. U.S.A. 1994, 91, 4519. (g) Kobayashi, S.; Hidaka, S.; Kawamura,
Y.; Ozaki, M.; Hayase, Y. J. Antibiot. 1998, 51, 323-327. (h) Kobayashi,
S.; Nakai, H.; Ikenishi, Y.; Sun, W.-Y.; Ozaki, M.; Hayase, Y.; Takeda, R.
J. Antibiot. 1998, 51, 328-332. (i) For an annual review see: Lewis, J. R.
Nat. Prod. Rep. 2000, 17, 57-84.
10.1021/ol000178q CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/26/2000

Over the years, a number of amino acid-based syntheses
of ∆2-thiazolines have been reported.2a,b,d,e,h,j-o,4 Notably,
Heathcock has used TiCl4 to synthesize 4-carboxy-4-methyl-
∆2-thiazolines from their corresponding R-methyl cysteine
derivatives via amide bond activation.2a,d,e,g As part of a
program directed at developing and applying biomimetic
methods (i.e., amide bond activation) for the syntheses of
peptide-derived heterocycles, we have investigated the scope
and limitations of TiCl4-mediated thiazoline ring formation
with racemization-prone precursors.
Efficiency in organic synthesis is important.5 Thus, reac-
tion conditions that remove sulfur protecting groups and
mediate cyclodehydration of cysteines to thiazolines are
highly desirable. Since trityl groups (Tr) are removed under
mild acidic conditions, oxophilic Lewis acids should effect
the desired tandem deprotection-heterocyclization.
a
Table 1. Dehydrocyclization of 1 Mediated by TiCl4
entry
temp (°C)
time (h)
yield (%)
% eeb
1
2
3
4
25
0
0
2
4
11
18
81
58
72
83
80
88
87
88
0
a Reactions were carried out using 3 equiv of TiCl4 in CH2Cl2.
b Enantiomeric excesses determined by chiral HPLC equipped with a
photodiode array detector and a Chiralcel OD column.
Thiazoline 2 was afforded in good yield with significant
racemization at 25 °C (entry 1, 81% yield, 80% ee). The
reaction proceeded more slowly at 0 °C; after 18 h, a yield
of 83% was realized with enhanced stereoselectivity at C(4)
(entry 4, 88% ee). Since product enantiomeric purity
measured as a function of reaction progress was almost
invariant, it appears that a partial loss of chirality occurs
during cyclodehydration (entries 2-4). This hypothesis is
supported by the fact that resubjecting product 2 to the
reaction conditions did not compromise its stereochemical
integrity.
To test this, fully protected cysteine derivative 1 was
synthesized (Scheme 1, eq 1) and treated with a variety of
Scheme 1a
To further probe the scope of this reaction, protected
cysteine N-amides 3-6 were synthesized (Scheme 1, eq 1).
Titanium(IV)-mediated tandem deprotection-dehydrocy-
clization reactions of 3-6 proceeded in moderate to excellent
yields (Table 2). The reaction with penicillamine analogue
3 afforded the highest chemical and optical yield, likely due
to the Thorpe-Ingold effect which increases the rate of
cyclization relative to competing racemization (entry 2; 96%
yield, 99% ee).7
A substituent effect was observed for the cyclodehydration
reactions of N-benzoylated starting materials (Table 2, entries
2 and 3). As expected, the presence of an electron-
withdrawing substituent (i.e., p-NO2) increased reactivity,
while an electron-donating substituent (i.e., p-OMe) de-
creased it (77% vs 28% yield). Moreover, racemization was
suppressed by the presence of an electron-donating group
and enhanced by an electron-withdrawing group. This can
be rationalized on the basis of the contribution of these
substituents to the reduced or the increased acidity of the
R-protons.
a Reagents: (i) TMSCHN2, MeOH:C6H6; (ii) Et2NH, CH3CN;
(iii) R1COCl (see tables for the structures of R1), DIEA, CH2Cl2;
(iv) Fmoc-L-Cys(Tr)-OH, HBTU, HOBT, collidine, DMF:CH2Cl2;
(v) PhCOCl, DIEA, CH2Cl2. Tr ) trityl.
oxophilic Lewis acids. While most Lewis acids successfully
removed the trityl group, only TiCl4 mediated both S-
deprotection and cyclodehydration (Scheme 2).6
Scheme 2
To ascertain the feasibility of one-pot multiple dehydro-
cyclizations, a fully protected Cys-Cys dipeptide was syn-
(5) Hudlicky, T.; Natchus, M. G. Org. Synth.: Theory Appl. 1993, 2,
1-25.
A summary of the reaction conditions used for the
(6) Typical experimental procedure: A solution of S-trityl-protected
cysteine N-amide 1 (0.125 mmol) in dry CH2Cl2 (2.5 mL) was treated with
TiCl4 (375 µL of a 1.0 M solution in CH2Cl2, 0.375 mmol) and stirred at
0 °C for 18 h. The reaction mixture was quenched with cold saturated
aqueous NaHCO3 (2×). The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were dried over MgSO4, filtered, and
concentrated. The resultant crude product was purified by flash chroma-
tography (30% EtOAc/hexanes) to afford 2 as a colorless oil (23.0 mg,
0.104 mmol, 83%). Data for 2: 1H NMR (500 MHz, CDCl3) δ 7.88-7.26
(m, 5H, Ar), 5.29 (ABX, 1H, JAX ) 9.0, JBX ) 9.4 Hz, CH-N), 3.84 (s,
3H, O-CH3), 3.72 (ABX, 1H, JAB ) 11.2, JAX ) 9.0 Hz, CH-S), 3.64 (ABX,
1H, JAB ) 11.2, JBX ) 9.4 Hz, CH-S); 13C NMR (125 MHz, CDCl3) δ
171.3, 171.0, 132.6, 131.7, 128.6, 128.5, 78.5, 52.8, 35.3; HRMS (MALDI-
FTMS) calcd for C11H12NO2S (M + H+) 222.0589, found 222.0591.
(7) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
1080.
synthesis of thiazoline 2 from 1 is presented in Table 1.
(3) For a recent review, see: Sinha Roy, R.; Gehring, A. M.; Milne, J.
C.; Belshaw, P. J.; Walsh, C. T. Nat. Prod. Rep. 1999, 16, 249-263.
(4) (a) Hirotsu, Y.; Shiba, T.; T.; K. Bull. Chem. Soc. Jpn. 1967, 40,
2945. (b) Hirotsu, Y.; Shiba, T.; Kaneko, T. Bull. Chem. Soc. Jpn. 1970,
43, 1870. (c) Suzuki, N.; Izawa, Y. Bull. Chem. Soc. Jpn. 1976, 49, 3155-
3158. (d) Inami, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1985, 58, 352. (e)
North, M.; Pattenden, G. Tetrahedron 1990, 46, 8267. (f) Galeotti, N.;
Montagne, C.; Poncet, J.; Jouin, P. Tetrahedron Lett. 1992, 33, 2807. (g)
Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267. (h) Wipf, P.; Fritch,
P. C. Tetrahedron Lett. 1994, 35, 5397. (i) Lafargue, P.; Guenot, P.;
Lellouche, J.-P. Synlett 1995, 171-172. (j) Charette, A. B.; Chua, P. J.
Org. Chem. 1998, 63, 908-909. (k) Ino, A.; Murabayashi, A. Tetrahedron
1999, 55, 10271-10282.
3290
Org. Lett., Vol. 2, No. 21, 2000

terminal thiazoline ring, as well as the oxidized nature of
the internal oxazole ring (Figure 1). A similar result was
Table 2. Dehydrocyclization of Protected Cysteine Analogues
Mediated by TiCl4
Figure 1. X-ray crystal structure of bis-heterocycle 12.
observed by Charette et al. in their synthesis of bis-thiazolines
using a different strategy.4j Apparently, contiguous thiazoline
rings with H at the C(4) position are susceptible to rapid
oxidation.8
To probe racemization at the C(2)-exomethine carbon and
to possibly gain insight into the selective oxidation observed
in the synthesis of 12, fully protected dipeptide 13 was
synthesized.9 Deprotection-cyclodehydration of compound
13 using TiCl4 afforded a 1:1 mixture of the corresponding
diastereomeric thiazolines (60% yield) (Scheme 4). Race-
Scheme 4
a Reactions were carried out using 3 equiv of TiCl4 at 0 °C for 18 h.
b Enantiomeric excesses determined by chiral HPLC equipped with a
photodiode array detector and a Chiralcel OD column. c The reaction was
carried out using 3 equiv of TiCl4 at 0 °C for 4 h. d The reaction was carried
out using 3 equiv of TiCl4 at 25 °C for 11 h. Tr ) trityl.
mization of the C(2)-exomethine chiral center limits the
utility of this approach for the formation of thiazolines within
peptides.
In the selective oxidation of a thiazoline ring associated
with the TiCl4-mediated synthesis of 12, it is reasonable to
assume that the bis-thiazoline intermediate readily tautomer-
izes, which may predispose thiazoline ring B to oxidation
(Scheme 5).
thesized (Scheme 1, eq 2). Reaction of Cys-Cys dipeptide
11 with TiCl4 proceeded at 25 °C with the desired bis-
deprotection-dehydrocyclization (Scheme 3). Interestingly,
Scheme 5
Scheme 3
the reaction efficiently produced the corresponding thiazole-
thiazoline heterocycle 12 (38% yield, 97% ee, >99% ee after
a single crystallization). Single-crystal X-ray analysis of bis-
heterocycle 12 confirmed the absolute configuration of the
In conclusion, the TiCl4-mediated tandem deprotection-
cyclodehydration of simple trityl-protected cysteine N-amide
derivatives is a versatile procedure for the synthesis of
thiazolines in moderate to high yields with generally good
Org. Lett., Vol. 2, No. 21, 2000
3291

stereoselectivities. This method is also useful for conversion
of protected Cys-Cys dipeptides into linearly fused thiazole-
thiazoline heterocycles (e.g., 11 f 12). The most significant
limitation identified is racemization at the C(2)-exomethine
position associated with the TiCl4-mediated synthesis of
thiazolines within peptides.
for use of his analytical chiral HPLC, David Lewy for
assistance, and Dr. Raj K. Chadha for the X-ray structure
determination of 12.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1-12 and
an X-ray structure report for 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge the
Skaggs Institute of Chemical Biology for generous financial
support and the Hereditary Disease Foundation for a post-
doctoral fellowship (H.R.). We thank Professor Dale Boger
OL000178Q
(8) Air oxidation of thiazoline rings in tantazole A, tantazole I, and
mirabazole A during their isolation and purification has been reported to
afford thiazoles (see: refs 1a and 1b).
(9) Compound 13 was synthesized in solution by standard protocols using
HOBT (1.1 equiv), HBTU (1.1 equiv), and DIEA (2.1 equiv) in DMF to
mediate amide bond formation.
3292
Org. Lett., Vol. 2, No. 21, 2000