A straightforward approach towards thiazoles and endothiopeptides via Ugi reaction

Article abstract of DOI:10.1039/b507028g

Endothiopeptides can easily be obtained via Ugi reaction using thio acids as acid components. If isonitriles with an acetal group are applied, the endothiopeptides can directly be converted into thiazoles using TMSCl-NaI under microwave irradiation. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b507028g

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A R T I C L E
A straightforward approach towards thiazoles and endothiopeptides
via Ugi reaction†
Uli Kazmaier* and Stefanie Ackermann
Institut fu¨r Organische Chemie, Universita¨t des Saarlandes, D-66123 Saarbru¨cken, Germany.
E-mail: u.kazmaier@mx.uni-saarland.de; Fax: +49 681 302 2409; Tel: +49 681 302 2409
Received 18th May 2005, Accepted 29th June 2005
First published as an Advance Article on the web 26th July 2005
Endothiopeptides can easily be obtained via Ugi reaction using thio acids as acid components. If isonitriles with an
acetal group are applied, the endothiopeptides can directly be converted into thiazoles using TMSCl–NaI under
microwave irradiation.
Introduction
Peptides with backbone modifications are highly interesting
from a pharmaceutical point of view and have therefore attracted
considerable interest in recent years.1 The replacement of
proteolysable amide bonds has been an especially successful
strategy in the design of novel enzyme inhibitors.2 Thioamides,
for example, have been used as amide bond surrogates in a
number of biologically active peptides such as cyclosporine,3
enkephaline4 and others.5 They have also been incorporated into
Scheme 1 Thiazole synthesis via Ugi reaction.
inhibitors of carboxypeptidase A,6 triosephosphate isomerase,7
angiotensin-converting enzyme8 or HIV-1 protease.9 Exchange
Results and discussion
of a normal amide bond by a thioamide bond results in a higher
Our group has been involved in amino acid and peptide
proteolytic stability,6,8 and also a higher rotation barrier around
syntheses for several years,23 also taking advantage of the Ugi
the C–N bond,10 which has an influence on the conformation,
reaction24 as a straightforward approach to obtain complex
especially of cyclic peptides.7 If the thioamide bond is located
peptide structures.25 In combination with ring closing metathe-
between an amino acid/peptide and a serine, cyclisation can
sis, this approach was also used for the synthesis of cyclic
occur giving rise to thiazoline amino acids,11 which can be
peptides.26 Herein we report on the application of Ugi reactions
for the synthesis of endothiopeptides and their conversion
into thiazoles. We began our investigations concerning the
endothiopeptide synthesis with the commercially available thio
oxidized to thiazole amino acids A.12 Such thiazolines and
thiazoles are widely found in nature, especially in cyclic peptides
of marine origin.13 Thiazole amino acids of type A are generally
located in the middle of a peptide chain, while unsubstituted
acids, thio acetic acid and thio benzoic acid, using benzylamine
thiazoles are found at the C-terminal position of several natural
as standard amine component (Scheme 2). Ethyl isocyanoac-
products,14 such as dolastatin 1815 or the virenamides (B).16
etate 1a was chosen because it gives rise directly to glycine
incorporated endothiodipeptides 2. As carbonyl components we
chose aliphatic and aromatic aldehydes as well as cyclohexanone
as a representative ketone.
Based on the high pharmaceutical potential of these peptides,
many synthetic studies have been undertaken towards their
synthesis. Endothiopeptides, containing a thioamide bond, can
be obtained either by direct thionation with Lawesson’s reagent17
or via thioacylation with alkyl dithioesters18 and thio acids or
derivatives.19 Ring opening of azirines with thio acids gives direct
access to endothiopeptides containing quaternary amino acids
such as Aib.20 The use of enzymatic coupling of endothiopeptide
Scheme 2 Synthesis of endothiopeptides via Ugi reaction.
methyl esters with the amino terminus of peptides has also been
reported.21
Several examples are given in Table 1. In general, the best
Besides the “classical protocol” via cyclisation mentioned
above, the thiazole amino acids of type A can also be obtained
in a combinatorial way via Ugi reaction using thiocarboxylic
acids and a suitable isonitrile (Scheme 1).22 In principle, an
endothiopeptide should be formed as an intermediate, but this
could not be isolated under the reaction conditions used.
results were obtained with sterically demanding aldehydes such
as pivalaldehyde (entries 3, 4), which are in good agreement with
previous observations made with carboxylic acids. Thio benzoic
acid was found to be slightly superior to thio acetic acid, but the
overall yields were very good, and the products were formed in
relatively pure form.
Especially in the reactions with pivalaldehyde, the products
showed a high tendency to crystallise, in general, precipitated
directly from the reaction mixture. Replacing benzylamine by
ammonia (entries 7, 8) resulted in a significantly lower yield.
† Electronic supplementary information (ESI) available: preparation
and analytical/spectroscopic data of all peptides 2 and 3 as well as
the thiazoles 6. See http://dx.doi.org/10.1039/b507028g
3 1 8 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 4 – 3 1 8 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Online
Table 1 Endothiopeptides obtained by Ugi reaction
Entry
R1
R2
R3
R4
Isonitrile
Peptide
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me
Ph
Me
Ph
Ph
Ph
Me
Ph
Me
Me
Ph
Me
Me
Ph
Bn
Bn
Bn
Bn
Bn
Bn
H
iPr
iPr
tBu
tBu
Ph
H
H
H
H
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
2a
2b
2c
2d
2e
2f
68
82
72
89
65
55
31
35
81
51
71
55
92
80
71
H
–(CH2)5–
H
H
H
H
H
tBu
tBu
tBu
iPr
2g
2h
3a
3b
3c
3d
3e
3f
H
Bn
Bn
Bn
Bn
Me
Me
H
tBu
–(CH2)5–
tBu
tBu
tBu
H
H
H
Ph
3g
Ammonia is known to be a marginal substrate for Ugi reactions,
undergoing a wide range of side reactions.25b,d
With BF3 and HC1 a clean conversion was observed, and
the thiazoline was obtained in nearly quantitative yield. We
therefore tried to generate the thiazole 6a from thiazoline 5a.
According to Jacobi et al.27 methanesulfonic acid should be the
acid of choice for this purpose. Indeed, with this acid we were
able to isolate some thiazole 6a, albeit in only 17% yield, which
was close to the results reported in the literature. Unfortunately,
decomposition was the major problem, probably the thiazole
is not stable under these relatively drastic acidic conditions.
We therefore thought that cleavage of the thioacetal to the
thiosemiacetal might be an interesting option. This brought us
to a reagent which is generally used for ether cleavage: TMSCl–
NaI as a substitute for TMSI.28 With this reagent combination
in acetonitrile, the required thiazole 6a indeed was obtained
in 55% yield. Prolonging the reaction time unfortunately did
not result in higher yields but rather complete decomposition.
This clearly indicates that it is the lability of the thiazole that
causes the problems. Obviously it is important to shorten the
reaction time to get good results, and we therefore investigated
the same reaction under microwave irradiation. After 10 min (50
W) a complete conversion of the thiazoline 5a was observed and
thiazole 6a was obtained in 80% yield.
Encouraged by the good results obtained with benzylamine we
also varied the isonitrile component. Anticipating application
to subsequent thiazole synthesis, we chose the related acetal
1b. The yields were comparable to the results obtained with
isocyanoacetate 1a (entries 9 to 15). With this isonitrile we
also varied the amine component. Allylamine, for example,
gave yields in the range of 76–90%, but the products obtained
were unstable and decomposed on standing, some of them
rapidly. But with methylamine, which gives direct access to N-
methylated peptides, the results were excellent (entries 13, 14),
and even ammonia gave the expected product in good yield
(entry 15). With these endothiopeptides 3 in hand, we began
our investigations towards the thiazole synthesis. In principle,
under acidic conditions, the nucleophilic sulfur should attack the
acetal moiety providing thioacetal 5, which would then undergo
elimination yielding the expected thiazole 6 (Scheme 3). As a
test system we chose 3a and investigated the influence of the acid
used on the acetal cleavage (Table 2). Unfortunately, the reaction
stopped on the state of the thiazoline 5a, and no elimination was
observed under all conditions used.
In principle both steps, the thiazoline and the thiazole
formation, proceed under (Lewis) acidic conditions. This caused
us to subject the Ugi products 3 directly in the microwave
to the TMSCl–NaI treatment (Scheme 4) and the results are
summarized in Table 3. A few thioamides such as the N-allyl
derivatives mentioned before, or the derivative 3d were not stable
and decomposed completely, but the others gave the expected
thiazoles 6 in good to excellent yield.
Scheme 4 Direct conversion of endothiopeptides into thiazoles.
Table 3 Thiazoles obtained by microwave reaction
Scheme 3 Two step conversion of endothiopeptides into thiazoles.
Table 2 Acidic cyclisation of 3a
Acid
Solvent
Reaction time
Yield 5a (%)
Acetal
Thiazole
Time (min)
Yield (%)
10 mol% TsOH
1 equiv TiCl4
50% TFA
1 equiv BF3OEt2
10 mol% HCl
Acetone
Ether
CHC13
Ether
72 h
4 h
3 h
4 h
15 h
75
75
86
94
95
3a
3b
3c
3e
3g
6a
6b
6c
6e
6g
30
10
5
30
15
80
87
91
66
91
CH2C12
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 4 – 3 1 8 7
3 1 8 5

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(CI): calcd. for C19H30N2O3S ([M]+), 366.1978; found, 366.1978.
Elemental analysis: C19H30N2O3S (364.51) calcd.: C 62.61 H 7.74
N 7.69; found: C 62.10 H 7.49 N 7.57.
Conclusion
In conclusion we have shown that the application of thio acids in
Ugi reactions gives rise to endothiopeptides in one step with the
option of combinatorial synthesis. If suitable isonitriles are used,
these endothiopeptides can be converted into peptidic thiazoles
also in one step under microwave irradiation.
2-[l-(Acetyl-benzylamino)-2,2-dimethyl-propyl]-5-methoxy-4,5-
dihydrothiazole (5a)
Endothiopeptide 3a (1.10 g, 3.00 mmol) was dissolved in
CH2C12 (50 mL) and conc. HC1 (250 lL, 0.30 mmol) was
added dropwise. The reaction mixture was stirred overnight.
Then it was washed twice with saturated NaHCO3 solution and
once with brine. The organic layer was dried over NaSO4 and the
solvent was removed in vacuo. The crude product was purified by
column chromatography (hexanes–EtOAc = 7 : 3) and thiazoline
5a was◦obtained as a white solid (953 mg, 2.80 mmol, 95%), mp
71–73 C. 1H NMR (500 MHz, CDC13): d = 1.02 (s, 4.5H), 1.05
(s, 4.5H), 1.85 (s, 1.5H), 1.89 (s, 1.5H), 3.14 (s, 1.5H), 3.18 (s,
1.5H), 3.25 (dd, J = 16.7, 6.0 Hz, 0.5H), 4.08 (dd, J = 16.7,
6.0 Hz, 0.5H), 4.25 (dd, J = 17.0, 13.0 Hz, 1H), 4.50 (dd, J =
27.4, 17.7 Hz, 1H), 5.25 (m, 2H), 5.63 (s, 0.5H), 5.70 (s, 0.5H),
6.93–7.19 (m, 5H). 13C NMR (125 MHz, CDC13): d = 23.7,
23.9, 28.6, 38.5, 39.1, 51.3, 41.4, 56.6, 57.2, 61.1, 61.9, 73.2,
73.4, 92.8, 93.2, 126.3, 127.1, 127.4, 127.6, 129.3, 139.6, 139.9,
174.0, 174.4. HRMS (CI): calcd. for C18H26N2O2S ([M + H]+),
335.1793; found, 335.1784.
Experimental
Preparation of isonitrile 1b
Aminoacetadehyde dimethylacetal (21.0 g, 0.20 mmol) was
dissolved in ethyl formate (200 mL) and refluxed overnight.
After cooling to room temperature, the solvent was removed
in vacuo. The N-formylaminoacetaldehyde dimethylacetal was
obtained as a pale yellow liquid (26.0 g, 0.19 mol, 98%).
This formamide (20.0 g, 0.15 mol), was dissolved in CH2C12
(200 mL) together with triethylamine (45.5 g, 0.45 mol) and
the reaction mixture was cooled to 0 ◦C before POC13 (23.0 g,
0.15 mol) was added dropwise to the solution. The mixture
was allowed to warm to room temperature and after stirring
for 1 h at room temperature, Na2CO3 solution (150 mL, 20 g
in 100 ml water) was added and the mixture was stirred for
another hour at room temperature. Then water was added, the
layers were separated, and the organic layer was washed 3 times
with water. After drying the organic layer over Na2SC4, the
solvent was removed in vacuo. Distillation in high vacuo (kp0.15
=
General procedure for thiazole synthesis using microwaves
◦
50 C) provided the isonitrile 1b as a colourless liquid (9.76 g,
The endothiopeptide 3 (n mmol) was dissolved in acetonitrile
(10 n mL). Then TMSC1 (1.5 n mmol), and NaI (1.5 n mmol)
were added. The reaction mixture was irradiated in a sealed tube
in a focused microwave oven (CEM Discover) at 50 Watt for the
specified time. Water and CH2C12 were added to the mixture, the
layers were separated and the organic layer was washed with 10%
Na2S2O3 solution. After drying the organic layer over Na2SC4,
the solvent was removed in vacuo and the crude product was
purified by column chromatography.
1
85.0 mmol, 57%). H NMR (500 MHz, CDC13): d = 3.36 (s,
6H), 3.44 (d, J = 5.7 Hz, 2H), 4.54 (t, J = 5.7 Hz, 1 H). 13C
NMR (125 MHz, CDC13): d = 43.5, 54.4, 101.0, 158.5.
General procedure for Ugi reactions with thio acids
The aldehyde (n mmol) and the amine (n mmol) were dissolved
in alcohol (n mL, ethanol for Ugi products 2 and methanol for
Ugi products 3) and stirred for 15 min at room temperature.
Then the reaction mixture was cooled to 0 ◦C and the thio acid
(n mmol) was added followed by the isonitrile (n mmol). The
ice-bath was removed and the mixture was stirred overnight
at room temperature. Then CH2Cl2 was added and the organic
layer was washed twice with saturated Na2CO3 solution and 1 M
KHSO4 solution. After drying the organic layer over Na2SC4,
the solvent was removed in vacuo and the crude product was
purified by column chromatography and/or recrystallisation.
2-[l-(Acetyl-benzylamino)-2,2-dimethyl-propyl]-thiazole (6a)
After the general procedure for thiazole synthesis using mi-
crowaves, 6a was obtained after purification by column chro-
matography (hexanes–EtOAc = 7 : 3) in a 0.10 mmol range as a
white solid in 80% yield, mp 108–110 ◦C. 1H NMR (500 MHz,
CDC13): d = 1.06 (s, 9H), 1.86 (s, 3H), 4.60 (d, J = 17.3 Hz,
1H), 5.42 (d, J = 17.4 Hz, 1H), 6.19 (s, 1H), 6.61 (d, J = 6.9 Hz,
1H), 6.99–7.08 (m, 5H), 7.51 (d, J = 4.4 Hz, 1H). 13C NMR
(125 MHz, CDC13): d = 22.7, 27.9, 38.3, 50.4, 59.5, 118.6, 125.1,
126.4, 128.3, 138.7, 142.9, 165.7, 172.8. HRMS (CI): calcd.
for C17H22N2OS ([M]+), 302.1453; found, 302.1452. Elemental
analysis: C17H22N2OS (302.45) calcd.: C 67.51 H 7.33 N 9.26;
found: C 67.07 H 7.26 N 9.05.
Ethyl [2-(acetyl-benzylamino)-3-methyl-thiobutyryl]-
glycinate (2a)
According to the general procedure for thio Ugi reactions,
2a was obtained after purification by column chromatography
(hexanes–EtOAc = 6 : 4) in a 2.00 mmol range as a yellow oil in
68% yield. 1H NMR (500 MHz, CDC13): d = 0.67 (d, J = 6.1 Hz,
3H), 0.87 (d, J = 6.7 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H), 2.10 (s,
3H), 2,81 (bs, 1H), 4.18 (q, J = 7.0 Hz, 2H), 4.29 (dd, J = 13.1,
5.2 Hz, 2H), 4.35 (d, J4,5 = 4.9 Hz, 1H), 4.57 (s, 2H), 7.16–7.26
(m, 5H), 7.97 (bs, 1H). 13C NMR (125 MHz, CDC13): d = 14.1,
20.3, 28.3, 47.2, 61.6, 125.9, 127.5, 128.7, 138.7, 168.6, 173.8,
202.6. HMRS (CI): calcd. for C18H26N2O3S ([M]+), 350.1664;
found, 350.1653.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie as well as from Bayer AG
is gratefully acknowledged.
References
1 (a) A. F. Spatola, in Chemistry and Biochemistry of Amino Acids,
Peptides and Proteins, ed. B. Weinstein, Marcel Dekker, New York,
1983, vol. 7, ch. 5, pp. 267–357; (b) Peptides: Chemistry and Biology,
ed. N. Sewald and H.-D. Jakubke, Wiley-VCH, Weinheim, 2002,
ch. 7, pp. 339–378.
2 Reviews: (a) R. Hirschmann, Angew. Chem., 1991, 103, 1305–1330;
R. Hirschmann, Angew. Chem., Int. Ed. Engl., 1991, 30, 1278–1301;
(b) A. Giannis and T. Kolter, Angew. Chem., 1991, 105, 1303–1326;
A. Giannis and T. Kolter, Angew. Chem., Int. Ed. Engl., 1993, 32,
1244–1267; (c) J. Gante, Angew. Chem., 1994, 106, 1780–1802; J.
Gante, Angew. Chem., Int. Ed. Engl., 1994, 33, 1699–1720.
N-(2,2-Dimethoxy-ethyl)-2-(acetyl-benzylamino)-3,3-dimethyl-
thiobutyric acid amide (3a)
According to the general procedure for thio Ugi reactions, 3a
was obtained after recrystallisation from tert-butyl-methylether
in a 2 mmol range as white rhombic crystals in 81% yield, mp
110–112 ◦C. 1H NMR (500 MHz, CDC13): d = 1.06 (s, 9H), 2.13
(s, 3H), 3.33 (s, 6H), 3.70 (m, 2H), 4.23–4.54 (m, 4H), 7.19–7.26
(m, 5H), 10.82 (bs, 1H). 13C NMR (125 MHz, CD3OD): d =
23.4, 28.5, 38.2, 54.3, 54.7, 102.2, 129.6, 176.5, 201.5. HRMS
3 1 8 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 4 – 3 1 8 7

View Online
3 D. Seebach, S. Y. Ko, H. Kessler, M. Ko¨ck, M. Reggelin, P. Schneider,
M. D. Walkinshaw, J. J. Bolsterli and D. Beved, Helv. Chim. Acta,
1991, 74, 1953–1990.
4 (a) K. Clausen, A. F. Spatola, C. Lemieux, P. W. Schiller and S.-
O. Lawesson, Biochem. Biophys. Res. Commun., 1984, 120, 305–310;
(b) K. Clausen, M. Thorsen, S.-O. Lawesson and A. F. Spatola,
J. Chem. Soc., Perkin Trans. 1, 1984, 785–798; (c) G. Lajoie, F.
Lepine, S. Lemaire, F. Jolicoeur, C. Aube, O. Turcotte and B. Belleau,
Int. J. Pept. Protein Res., 1984, 24, 316–327.
Pettit, F. Hogan and D. L. Herald, J. Org. Chem., 2004, 69, 4019–
4022.
16 (a) A. R. Carroll, Y. Feng, B. F. Bowden, F. Hogan, D. L. Herald and
J. C. Coll, J. Org. Chem., 1996, 61, 4059–4061; (b) Y. Feng and B. F.
Bowden, Aust. J. Chem., 1997, 50, 337–340.
17 K. Clausen, M. Thorsen and S.-O. Lawesson, Tetrahedron, 1981, 37,
3635–3639.
18 J. Jurayj and M. Cushman, Tetrahedron, 1992, 48, 8601–8614 and
references cited.
5 C. I. Fincham, M. Higginbottom, D. R. Hill, D. C. Horwell, J. C.
O’Toole, O. S. Ratcliffe, D. C. Rees and E. Roberts, J. Med. Chem.,
1992, 35, 1472–1484.
6 (a) P. A. Bartlett, K. L. Spear and N. E. Jacobsen, Biochemistry, 1982,
21, 1608–1611; (b) P. Campbell and N. T. Nashed, J. Am. Chem. Soc.,
1982, 104, 5221–5226.
19 (a) T. Hoeeg-Jenson, C. E. Olsen and A. Holm, J. Org. Chem., 1994,
59, 1257–1263; (b) M. A. Shalaby, C. W. Grote and H. Rapoport,
J. Org. Chem., 1996, 61, 9045–9048.
20 (a) J. Lehmann, A. Linden and H. Heimgartner, Helv. Chim. Acta,
1999, 82, 888–908; (b) J. Lehmann and H. Heimgartner, Helv. Chim.
Acta, 1999, 82, 1899–1915.
7 H. Kessler, H. Matter, A. Geyer, H.-J. Diehl, M. Ko¨ck, G. Kurz, F. R.
Opperdoes, M. Callens and R. K. Wierenga, Angew. Chem., 1992,
104, 343–345; H. Kessler, H. Matter, A. Geyer, H.-J. Diehl, M. Ko¨ck,
G. Kurz, F. R. Opperdoes, M. Callens and R. K. Wierenga, Angew.
Chem., Int. Ed. Engl., 1992, 31, 328–330.
8 L. Maziak, O. Lajoie and B. Belleau, J. Am. Chem. Soc., 1986, 108,
182–183.
9 S. Yao, R. Zutshi and J. Chmielewski, Bioorg. Med. Chem. Lett.,
1998, 8, 699–704.
10 W. E. Stewart and T. H. Siddall III, Chem. Rev., 1970, 70, 517–551.
11 (a) P. Wipf and P. C. Fritch, Tetrahedron Lett., 1994, 35, 5397–5400;
(b) C. D. J. Boden and G. Pattenden, J. Chem. Soc., Perkin Trans. 1,
2000, 875–882.
21 C. Unverzagt, A. Geyer and H. Kessler, Angew. Chem., 1992, 104,
1231–1233; C. Unverzagt, A. Geyer and H. Kessler, Angew. Chem.,
Int. Ed. Engl., 1992, 31, 1229–1230.
22 (a) S. Heck and A. Do¨mling, Synlett, 2000, 424–426; (b) M.
Umkehrer, J. Kolb, C. Burdack and W. Hiller, Synlett, 2005, 79–82;
(c) A. Do¨mling and K. Illgen, Synthesis, 2005, 662–667.
23 Reviews: (a) U. Kazmaier, Liebigs Ann./Recl., 1997, 285–295;
(b) U. Kazmaier, in Bioorganic Chemistry, ed. U. Diederichsen,
T. K. Lindhorst, B. Westermann and L. A. Wessjohann, Wiley-
VCH, Weinheim, 1999, pp. 201–206; (c) U. Kazmaier, S. Maier and
F. L. Zumpe, Synlett, 2000, 1523–1535; (d) U. Kazmaier, in Claisen
Rearrangements, ed. M. Hiersemann and U. Nubbemeyer, Wiley-
VCH, Weinheim, 2005, pp. 231–297.
12 (a) M. North and G. Pattenden, Tetrahedron, 1990, 46, 8267–8290;
(b) L. A. McDonald, M. P. Foster, D. R. Phillips, C. M. Ireland,
A. Y. Lee and J. Clardy, J. Org. Chem., 1992, 57, 4616–4624; (c) For
a review on biosynthesis see: R. S. Roy, A. M. Gehring, J. C. Milne,
P. J. Belshaw and C. T. Walsh, Nat. Prod. Rep., 1999, 16, 249–263.
13 (a) J. P. Michael and G. Pattenden, Angew. Chem., 1993, 105, 1–24;
J. P. Michael and G. Pattenden, Angew. Chem., Int. Ed. Engl., 1993,
32, 1–23; (b) J. R. Lewis, Nat. Prod. Rep., 1997, 14, 371–398.
14 (a) D. Schipper, J. Antibiot., 1983, 36, 1076–1077; (b) W. D. Clark and
P. Crews, Tetrahedron Lett., 1995, 36, 1185–1188; (c) J. B. MacMillan,
E. K. Trousdale and T. F. Molinski, Org. Lett., 2000, 2, 2721–
2723.
24 (a) I. Ugi, Isonitrile Chemistry, Academic press, New York, 1971;
(b) A. Do¨mling and I. Ugi, Angew. Chem., 2000, 112, 3300–3344; A.
Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168–3210
and references cited therein.
25 (a) C. Hebach and U. Kazmaier, Chem. Commun., 2003, 596–597;
(b) U. Kazmaier and C. Hebach, Synlett, 2003, 1591–1594; (c) U.
Kazmaier and S. Ackermann, Synlett, 2004, 2576–2578; (d) R. Pick,
M. Bauer, U. Kazmaier and C. Hebach, Synlett, 2005, 757–760.
26 U. Kazmaier, C. Hebach, A. Watzke, S. Maier, H. Mues and V. Huch,
Org. Biomol. Chem., 2005, 3, 136–145.
27 (a) P. A. Jacobi, M. Egbertson, R. F. Frechette, C. K. Miao and K. T.
Weiss, Tetrahedron, 1988, 44, 3327–3338; (b) D. M. Spero and S. R.
Kapadia, Org. Chem., 1996, 61, 7398–7401.
15 (a) G. R. Pettit, J.-P. Xu, M. D. Williams, F. Hogan, J. M. Schmidt and
R. L. Cerny, Bioorg. Med. Chem. Lett., 1997, 7, 827–832; (b) G. R.
28 M. E. Jung and M. A. Lyster, J. Org. Chem., 1977, 42, 3761–3764.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 8 4 – 3 1 8 7
3 1 8 7