Enamides accessed from aminothioesters via a Pd(0)-catalyzed decarbonylative/β-hydride elimination sequence

Article abstract of DOI:10.1021/ol101620r

A facile synthesis of various enamides from aminothioesters via a palladium(0)-catalyzed decarbonylation/β-hydride elimination is reported. This protocol was applied to mercaptopyridyl C-terminal modified peptides for the generation of enamides without ep

Full text of DOI:10.1021/ol101620r

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4716-4719
Enamides Accessed from
Aminothioesters via a Pd(0)-Catalyzed
Decarbonylative/ꢀ-Hydride Elimination
Sequence
Geanna K. Min, Da´cil Herna´ndez, Anders T. Lindhardt, and Troels Skrydstrup*
Center of Insoluble Protein Structures (InSpin), Department of Chemistry, and
Interdispliscinary Nanoscience Center, Aarhus UniVersity, Langelandsgade 140,
8000 Aarhus C., Denmark
ts@chem.au.dk
Received July 14, 2010
ABSTRACT
A facile synthesis of various enamides from aminothioesters via a palladium(0)-catalyzed decarbonylation/ꢀ-hydride elimination is reported.
This protocol was applied to mercaptopyridyl C-terminal modified peptides for the generation of enamides without epimerization at stereogenic
centers.
Generation of enamides has been a long-standing interest to
the biological and chemical community as these motifs are
contained in several bioactive natural products (Figure 1).1
Enamides have also been used extensively as a building block
for further transformations.2 Several standard methods have
been reported in the literature for the synthesis of enamides
including Curtius rearrangement of R,ꢀ-unsaturated acyl
(1) (a) Galinis, D.; McKee, T.; Pannell, L.; Cardellina, J.; Boyd, M. J.
Org. Chem. 1997, 62, 8968. (b) Suzumura, K.; Takahashi, I.; Matsumoto,
H.; Nagai, K.; Setiawan, B.; Rantioamodjo, R.; Suzuki, K.; Nagano, N.
Tetradron Lett. 1997, 38, 7573. (c) Dekker, K.; Aiello, R.; Hirai, H.; Inagaki,
T.; Sakakibara, T.; Suzuki, Y.; Thompson, J.; Yamuchi, Y.; Kojima, N. J.
Antiobiot. 1998, 51, 14. (d) McKee, T.; Ganlanis, D.; Pannell, L.; Cardellina,
J.; Laasko, J.; Ireland, C.; Murray, L.; Capon, R.; Boyd, M. J. Org. Chem.
1998, 63, 7805. (e) Kunze, B.; Jansen, R.; Sasse, F.; Hofle, G.; Reichenbach,
H. J. Antiobiot. 1998, 51, 1075. (f) Kim., J.; Shin-ya, K.; Furihata, K.;
Hayakawa, Y.; Seto, H. J. Org. Chem. 1999, 64, 153. (g) Boyd, M.; Farina,
C.; Belfiore, P.; Gagliardi, S.; Kim, J.; Hayakawa, Y.; Beutler, J.; McKee,
T.; Bowman, B.; Bowman, E. J. Pharmacol. Exp. Ther. 2000, 297, 114.
(h) Sugie, Y.; Dekker, K. A.; Hirai, H.; Ichiba, T.; Ishiguro, M.; Shiomi,
Y.; Sugiura, A.; Brennan, L.; Duignan, J.; Huang, L. H.; Sutcliffe, J.;
Kojima, Y. J. Antibiot. 2001, 54, 1060. (i) Gournelif, D. C.; Laskarisb,
G. G.; Verpoorte, R. Nat. Prod. Rep. 1997, 14, 75. (j) Tschesche, R.;
Kauꢀmann, Fehlhaber, H. Chem. Ber. 1972, 105, 3094.
Figure 1. Natural products possessing the enamide functional unit.
azides3 and amide Petersen olefination,4 copper-mediated
amidation of vinylic halides,5 Horner Wittig and Wadsworth
Emmons reactions,6 and others7 as shown in Scheme 1.
10.1021/ol101620r  2010 American Chemical Society
Published on Web 09/24/2010

led us to speculate whether the formation of enamides could
be promoted by a Pd(0)-catalyzed decarbonylative/ꢀ-hydride
sequence.
Scheme 1. Previous Enamide Syntheses
Herein, we report the study leading to this method for the
preparation of enamides. Not only does this developed
method provide easy access to substituted enamides starting
from simple protected amino acid derivatives, but it also
allows the introduction of the possibility of C-terminal
modification of peptides.
Applying the conditions developed by Liebeskind without
the copper additive failed to yield enamide formation.
Various solvents, bases, and temperatures were screened with
these catalysts, and the reactions yielded only starting
material or decomposed material. Other palladium complexes
were investigated (Table 1). The allyl palladium chloride
However, some of these protocols require several steps to
generate the desired compounds, harsh conditions for ena-
mide formation, or the synthesis of unstable precursors.
In 2007, Liebeskind and co-workers reported a palladium/
copper facilitated cross coupling between aminothioesters
and organoboronic reagents.8 When using Pd(PPh3)4 and
copper thiocarboxylate at elevated temperatures, they re-
ported the formation of the desired cross coupled product
with the enamide obtained as the byproduct in Scheme 2.
Table 1. Initial Screening Experiments
entry
Pd source
PdCl2
liganda
NMR yield, %
1
2
3
4
5
6
7
8
9
PCy3
PCy3
13
0
Pd(dba)2
[(η3-allyl)PdCl]2 Dppf
14
28
21
70
41
29
56
42
[(η3-allyl)PdCl]2 DtBuPF
a
[(η3-allyl)PdCl]2 PtBu3
Scheme 2. Liebeskind’s Previous Studies
[(η3-allyl)PdCl]2 CataCXium A
[(η3-allyl)PdCl]2 Josiphos
[(η3-allyl)PdCl]2 CataCXium PinCy
[(η3-allyl)PdCl]2 CataCXium ABn
a b
,
10
[(η3-allyl)PdCl]2 PCy3
a 0.20 equiv phosphine. b 3.0 equiv DIPEA instead of Cy2NMe. a Ligand
structures:
Crisp and Bubner also have reported enamide formation
when attempting to cross couple aminothioesters with
organotin reagents using Pd(dppf)Cl2.9 These observations
(2) (a) Savarin, C.; Murray, J.; Dormer, P. Org. Lett. 2002, 4, 2071. (b)
Larock, R. C. ComprehensiVe Organic Transformations: A Guide to
Functional Group Preparations; Wiley-VCH: New York, 1999. (c) Fu¨rstner,
A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem.sEur. J. 2001, 7, 5286.
(3) (a) Brettle, R.; Mosedale, A. J. J. Chem. Soc., Perkin Trans. 1 1988,
2185. (b) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407. (c) Wieber, G. M.;
Hegedus, L. S.; Akermark, B.; Michalson, E. T. J. Org. Chem. 1989, 54,
4649.
(4) (a) Cuevas, J. C.; Patil, P.; Snieckus, V. Tetrahedron Lett. 1989,
30, 5841. (b) Palomo, C.; Aizpurua, J. Md.; Legido, M.; Picard, J. P.;
Dunogues, J.; Constantieux, T. Tetrahedron Lett. 1992, 33, 3903. (c)
Furstner, A.; Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3, 3955.
(5) (a) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. Chem. Lett. 1991,
8, 1443. (b) Shen, R.; Porco, J. A. Org. Lett. 2000, 2, 1333. (c) Han, C.;
Shen, R.; Shun, S.; Porco, J. A., Jr. Org. Lett. 2004, 6, 27. (d) Jiang, L.;
Job, G.; Klapars, A.; Buchwald, S. Org. Lett. 2003, 5, 3667.
(6) (a) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett. 1993,
34, 1479. (b) Paterson, I.; Cowden, C.; Watson, C. Synlett 1995, 2009.
(7) (a) Gooꢀen, L.; Blanchot, M.; Salih, K.; Gooꢀen, K. Synthesis 2009,
2283. (b) Gooꢀen, L.; Blanchot, M.; Salih, K. Angew. Chem., Int. Ed. 2008,
47, 8492. (c) Couladouros, E.; Moutsos, V. Tetrahedron Lett. 1990, 40,
7027. (d) Matusmura, Y.; Ohishi, T.; Sonoda, C.; Maki, T.; Watanabe, M.
Tetrahedron 1997, 53, 4579. (e) Kimber, M. Org. Lett. 2010, 12, 1128. (f)
Klapars, A.; Campos, K.; Cheng-yi, C.; Volante, R. Org. Lett. 2005, 7,
1185.
dimer and dppf (entry 3) achieved 14% isolated yield of the
desired enamide product 2a. Various other ligands, mono-
dentate and bidentate, were screened with the same palla-
dium(II) complex. Using CataCXium A (entry 6) provided
a 70% NMR yield. After screening solvents (THF, PhMe,
and dioxane) with allylpalladium chloride dimer and Cat-
aCXium A at various temperatures with various bases, using
diisopropylethylamine at 100 °C in dioxane for 18 h was
determined as the optimal conditions for this system.
(8) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.; Liebeskind,
L. J. Am. Chem. Soc. 2007, 129, 1132.
(9) Crisp, G. T.; Bubner, T. P. Synth. Commun. 1990, 20, 1665.
Org. Lett., Vol. 12, No. 21, 2010
4717

Various leaving groups were also screened as shown in
Table 2. When subjected to the palladium decarbonylative
Table 3. Enamide Synthesis from Amino Acids
Table 2. Varying the Nature of the Leaving Group
a Isolated yields of the trans- and cis-isomers. b The cis-isomer was
inseparable from the phosphine ligand on silica flash chromatography.
conditions, 2-mercaptopyridine 1c (entry 3) and 4-mercap-
topyridine 1d (entry 4) showed complete consumption of
starting material after 18 h and yielded the enamide product
in good yields. 4-Mercaptopyridine aminothioester 1d pro-
vided a more stable starting material, and when subjected to
the palladium decarbonylative conditions, a good 77%
isolated yield of 2 was obtained.
Using these optimized conditions, other aminothioesters
were then investigated, the results of which are depicted in
Table 3. The palladium decarbonylative method was applied
to a number of aminothioesters that contain aromatic chains,
heterogroups, and alkyl groups, furnishing the enamides in
moderate to good yields. In most cases, the trans-isomer was
isolated as the major product except in the case of entries 1
and 2, which favored the cis-product. In these cases, the cis
isomers were preferred presumably due to product stabiliza-
tion gained from hydrogen bonding between the amide and
the carbonyl substituent. The aminothioesters 3c-e (entries
3-5), in which R1 or R2 was aromatic, provided product
yields in the range of 74-77%. With R1 or R2 as an alkyl
chain, the yields dropped slightly to 51-64% with the
formation of the more highly substituted enamides furnishing
the better isolated yields, while the least substituted example
(entry 13) provided a 29% isolated yield of the vinyl amide.
Interestingly, in the case of the glutamic thioester (entry 6),
when presented with the possibility of double bond migration
in order to be in conjugation with the carboxylate group,
the reaction yielded only the desired enamide product.
This method was also applied to small peptide chains with
an aminothioester at the C-terminal end, providing 58-72%
yields of the desired enamides 5-7 depicted in Figure 2.
The method also works with nonstandard amino acids, such
a SAr ) 4-mercaptopyridine. b All trans:cis ratios in parentheses were
determined by isolated yield of each by flash chromatography except for
isoleucine and unprotected tryptophan. For isoleucine and unprotected
tryptophan derivatives, the trans/cis-isomers were inseparable.
as one containing a 2,2,2-trifluoroethyl side-chain, yielding
the volatile enamide 8 in a 21% yield.
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Org. Lett., Vol. 12, No. 21, 2010

aminothioesters and can potentially be further applied toward
the synthesis of various bioactive natural products that exhibit
this motif.
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foun-
dation, the Danish Council for Independent Research/Natural
Sciences, the Lundbeck Foundation, the Carlsberg Founda-
tion, and Aarthus University. D.H. thanks the Gobierno de
Espan˜a (MICINN) for a posdoctoral contract (Programa
Nacional de Movilidad de Recursos Humanos del Plan
nacional de I+D+I 2009-2011). We also thank Solvias for
a generous gift of ligands.
Figure 2. Peptide and unconventional amino acid functionalization.
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, we have demonstrated a facile way of
synthesizing enamides from aminothioesters via a palladium-
catalyzed decarbonylative/ꢀ-hydride elimination process in
moderate to good yields. This method is applicable to various
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