Complex α-pyrones synthesized by a gold-catalyzed coupling reaction

Article abstract of DOI:10.1002/anie.200703276

(Chemical Equation Presented) Sequential alkyne activation of readily available propargyl propiolates by a gold(I) catalyst yields compounds with α-pyrone skeletons (see scheme). An intermediate oxocarbenium ion converts into distinct products by two path

Full text of DOI:10.1002/anie.200703276

Communications
DOI: 10.1002/anie.200703276
Cascade Reactions
Complex a-Pyrones Synthesized by a Gold-Catalyzed Coupling
Reaction**
Tuoping Luo and Stuart L. Schreiber*
Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
We have been exploring a strategy for the synthesis of small
molecules with properties that increase the probability of
success in all facets of probe- and drug-discovery pipelines,
including discovery, optimization, and manufacturing.[1] This
strategy involves 1)the synthesis of building blocks with
functionality suitable for subsequent “coupling” and “pair-
ing” steps, 2)intermolecular coupling reactions that join the
building blocks in all stereochemical combinations, and
3)intramolecular pairing reactions that join different combi-
nations of functional groups to yield diverse skeletons.[2]
Herein, we describe a multicomponent coupling reaction
that we believe is well-suited for the coupling phase of this
strategy, as it yields, among other substances, complex and
diverse a-pyrones, which are core elements found in many
biologically active compounds.[3]
Scheme 1. Syntheses of trisubstituted a-pyrones by transition-metal-
catalyzed cascade reactions.
Convergent syntheses[4] of a-pyrones have traditionally
involved the lactonization of ketoesters.[5] Transition-metal-
catalyzed cycloaddition[6] and annulation reactions[7] are
recent alternatives that have attracted much attention, but
most are limited by the resulting poor regioselectivity or the
requirement for harsh reaction conditions.
We envisioned that the readily accessible propargyl
propiolate 1 could be converted to different products by a
cascade process (Scheme 1).[8] The [3,3] sigmatropic rear-
rangement of 1 catalyzed by a late transition metal would
generate an enyne allene A.[9] A 6-endo-dig cyclization would
be induced by the activation of the alkyne moiety in A to give
the oxocarbenium intermediate B. In one possible pathway,
elimination (ꢀ, Scheme 1)would afford a vinyl a-pyrone 2.
1
We anticipated that the intermediate B could also be trapped
by a variety of nucleophiles. We hypothesized that the
trapping of electrophilic intermediate B, which can in
principle be attacked at three distinct sites (ꢀ, ꢀ, and ꢀ,
2
3
4
Scheme 1), could be controlled by using different nucleo-
philes and reaction conditions. The successful realization of
many of these concepts is described.
A similar [3,3] sigmatropic rearrangement followed by a
6-endo-dig cyclization cascade reaction has been reported by
Toste and co-workers for the synthesis of aromatic ketones.[9a]
Stimulated by this result, we attempted to use the reported
[*] Prof. Dr. S. L. Schreiber
Broad Institute of Harvard and MIT
Howard Hughes Medical Institute
Department of Chemistry and Chemical Biology
Harvard University
7 Cambridge Center, Cambridge, MA 02142 (USA)
Fax: (+1)617-324-9601
silver(I)catalysts to achieve the rearrangement of
1a
(Table 1, entry 1). However, the desired vinyl a-pyrone 2a
was obtained in low yield. In contrast, the widely used cationic
gold(I)catalyst (Table 1, entry 2) [10] provided 2a in 61% yield
at room temperature. At higher temperatures, 2a was
obtained in 81% yield (Table 1, entry 3), whereas a compar-
ison experiment that used only 5% AgSbF6 afforded a low
yield of 2a (Table 1, entry 4).
E-mail: stuart_schreiber@harvard.edu
T. Luo
Broad Institute of Harvard and MIT
Department of Chemistry and Chemical Biology
Harvard University
7 Cambridge Center, Cambridge, MA 02142 (USA)
Increasing the temperature in 1,2-dichloroethane (DCE)
[**] The NIGMS-sponsored Center of Excellence in Chemical Method-
ology and Library Development (Broad Institute CMLD) enabled
this research. We thank Ben Stanton, Arturo Vegas, Dr. Weiping
Tang, Dr. Thomas Nielsen, and Dr. Xiang Wang for helpful
discussions. T.L. thanks Chris Johnson at the Broad Institute for the
help with SFC/MS. S.L.S. is an Investigator with the Howard
Hughes Medical Institute.
led to
a decreased yield (Table 1, entry 5). Pyridine
(10 mol%)was added in the hope of accelerating the
elimination pathway (Table 1, entry 6), but this resulted
instead in the inhibition of the reaction, presumably by
inactivation of the cationic gold catalyst by pyridine coordi-
nation.[11] Polar or coordinating solvents decreased the
reaction efficiency and acetonitrile inhibited the reaction
(Supporting Information).[10b] The reaction mixture converted
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Optimization of reaction conditions for the rearrangement of 1a
into 2a.
The rearrangement of propargyl propiolates 1b–g gave
the desired vinyl a-pyrones 2b–g in 65–84% yield (Table 2).
The olefin moiety in 1 f did not interfere with the cascade
reaction despite the precedent of reactions involving 1,6-
enynes.[10b,13] Substrate 1h resulted in a less efficient reaction,
and gave 2h in only 40% yield, most likely because of an
intramolecular attack of the cationic intermediate by the ketal
oxygen atom.[14]
We also determined that the cationic intermediate B can
be trapped by electron-rich arenes and heteroarenes in a
Friedel–Crafts-type reaction. Performing the model reaction
Entry
Catalyst
Conditions
Yield [%][a]
1a
2a
[b]
1
2
3
4
5
6
7
8
9
AgSbF6
CH2Cl2, RT
CH2Cl2, RT
CH2Cl2, reflux
CH2Cl2, reflux
1,2-DCE, 608C
CH2Cl2, RT
95
0
0
25
0
96
–
trace
61
81
11
67
0
[(Ph3P)AuCl]/AgSbF6
[(Ph3P)AuCl]/AgSbF6
AgSbF6
[(Ph3P)AuCl]/AgSbF6
[(Ph3P)AuCl]/AgSbF6
[(Ph3P)AuCl]/AgSbF6
[(Ph3PAu)3O]BF4
[(Ph3P)AuNTf2]
[(Ph3P)AuCl]/AgOTf
[c]
[d]
THF, 408C
–
[e]
CH2Cl2, reflux
CH2Cl2, reflux
CH2Cl2, reflux
95
0
0
0
45
48
10
[a] Yields of isolated product after column chromatography. [b] 2 mol%
PPh3, 1.5 equiv MgO as additive. [c] 10 mol% pyridine as additive.
[d] The reaction mixture became vigorous and solidified. [e] 2 mol%
catalyst.
to a gel when THF was used as the solvent (Table 1, entry 7),
probably as a result of the polymerization of THF induced by
reactive cationic species.[12] Three other gold(I)species were
tested (Table 1, entries 8–10), but none was superior to
[(Ph3P)AuCl]/AgSbF6 used in the model reaction.
Scheme 2. Racemic products result from nonracemic propargyl propio-
lates.
Table 2: Gold(I)-catalyzed rearrangement of propargyl propiolates to vinyl a-pyrones.[a]
Substrate Product Substrate Product
with
5 mol%
[(Ph3P)AuCl]/
AgSbF6 at room temperature in
the presence of two equivalents of
trimethoxybenzene afforded the a-
pyrone 3a in 82% yield (Table 3).
None of the rearrangement prod-
uct 2a, or the products resulting
from nucleophilic attack at the
other two positions (ꢀ and ꢀ,
3
4
Scheme 1), was observed. The
addition of the aromatic ring to
the alkyne[15] does not interfere
with the tandem reaction. Com-
pound 3a was not detected when a-
pyrone 2a was subjected to these
reaction conditions, which indi-
cates that 2a is not an intermediate
in the formation of 3a.
Electron-rich aromatics and
heteroaromatics, such as indole,
furan, and benzofuran, are also
suitable nucleophiles in the Frie-
del–Crafts-type reaction, affording
3b–h in 59–85% yields (Table 3).
Note that 3a–h mimic the structure
of diaryl methanes, which have a
[a] Reaction conditions: propargyl propiolate (0.05m), [(Ph3P)AuCl]/AgSbF6 (5 mol%), CH2Cl2, reflux,
12 h.
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Table 3: Gold(I)-catalyzed syntheses of trisubstituted a-pyrones from propargyl propiolates.[a]
Substrate/Nu Product Substrate/Nu Product
whereas the major product, tricy-
clic compound 4, was obtained in
69% yield (Scheme 3). As 2j was
not converted into 4 under the
same conditions,
4
apparently
results from a 1,2-hydride shift in
intermediate C, thus yielding ter-
tiary carbocation D, which is trap-
ped by the phenyl group in an
intramolecular
Friedel–Crafts
reaction (Scheme 3).[18]
As the propargyl propiolates
used in these multicomponent cou-
pling reactions can be readily syn-
thesized from terminal alkynes and
aldehydes, which are among the
most highly varied and abundant
building blocks, we anticipate that
this coupling reaction will be well-
suited for the strategy noted in the
Introduction.
Two
additional
observations reinforce this expect-
ation. First, our preliminary studies
suggest that trapping the inter-
mediate oxocarbenium ion with
alcohol-based nucleophiles results
in attack at the lactone carbonyl
carbon atom, which results in an
alternative skeleton. Second, stra-
tegic placement of suitable func-
tionality in the building blocks
[a] Reaction conditions: propargyl propiolate (0.05m), nucleophile (Nu), [(Ph3P)AuCl]/AgSbF6
(5 mol%), CH2Cl2, RT, 24 h.
allows functional-group pairing reactions that enable
further skeletal diversification. To illustrate this concept,
coupling product 3k undergoes a ring-closing metathesis
to yield the polycyclic a-pyrone 5 (Scheme 4). We are
currently exploring the potential of these reaction pro-
cesses in diversity syntheses and determining the assay
Scheme 3. Cascade process yielding a tricyclic a-pyrone.
broad spectrum of biological activities.[16] The structure of 3d
was verified by X-ray analysis.[17]
When the enantiopure propargyl propiolates (R)-1e and
(R)-1i were subjected to the same reaction conditions in the
presence of electron-rich heteroarenes, racemates of 3e and
3i were obtained (Scheme 2). This result suggests that the
nucleophile bonds to both enantiofaces of the oxocarbenium
B with equal facility.
Scheme 4. Intramolecular functional-group pairing reaction involv-
ing substituents attached to distinct building blocks prior to the
intermolecular coupling reaction (cf. “build/couple/pair strategy”[2]).
When 1j was subjected to the reaction conditions,
trisubstituted a-pyrone 2j was obtained in only 16% yield,
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Leseurre, J.-P. GenÞt, V. Michelet, Angew. Chem. 2006, 118,
performance of the resulting products using many small-
molecule screens.
7587 – 7590; Angew. Chem. Int. Ed. 2006, 45, 7427 – 7430; c)S.
Park, D. Lee, J. Am. Chem. Soc. 2006, 128, 10664 – 10665; d)D. J.
Gorin, P. DubØ, F. D. Toste, J. Am. Chem. Soc. 2006, 128, 14480 –
14481; e)J.-J. Lian, P.-C. Chen, Y.-P. Lin, H.-C. Ting, R.-S. Liu, J.
Am. Chem. Soc. 2006, 128, 11372 – 11373; f)J. H. Lee, F. D.
Toste, Angew. Chem. 2007, 119, 930 – 932; Angew. Chem. Int. Ed.
2007, 46, 912 – 914; g)C.-C. Lin, T.-M. Teng, A. Odedra, R.-S.
Liu, J. Am. Chem. Soc. 2007, 129, 3798 – 3799; h)D. J. Gorin,
F. D. Toste, Nature 2007, 446, 395 – 403.
Received: June 22, 2007
Published online: September 24, 2007
Keywords: cascade reactions · cyclization · gold · pyrones ·
.
rearrangement
[11] S. E. Thwaite, A. Schier, H. Schmidbaur, Inorg. Chim. Acta 2004,
357, 1549 – 1557.
[12] S. Kobayashi, K. Morikawa, T. Saegusa, Macromolecules 1975, 8,
386 – 390.
[1] For examples, see: a)N. Kumagai, G. Muncipinto, S. L.
Schreiber, Angew. Chem. 2006, 118, 3717 – 3720; Angew. Chem.
Int. Ed. 2006, 45, 3635 – 3638; b)D. A. Spiegel, F. C. Schroeder,
J. R. Duvall, S. L. Schreiber, J. Am. Chem. Soc. 2006, 128, 14766 –
14767.
[2] T. E. Nielsen, S. L. Schreiber, Angew. Chem., DOI: 10.1002/
ange.200703073; Angew. Chem. Int. Ed., DOI: 10.1002/
anie.200703073.
[3] a)J. M. Dickinson, Nat. Prod. Rep. 1993, 10, 71 – 98; b) P. S.
Steyn, F. R. van Heerden, Nat. Prod. Rep. 1998, 15, 397 – 413;
c)G. P. McGlacken, I. J. Fairlamb, Nat. Prod. Rep. 2005, 22, 369 –
385; d)C. E. Salomon, N. A. Magarvey, D. H. Sherman, Nat.
Prod. Rep. 2004, 21, 105 – 121; e)M. J. van Raaij, J. P. Abrahams,
A. G. W. Leslie, J. E. Walker, Proc. Natl. Acad. Sci. USA. 1996,
93, 6913 – 6917; f)P.-L. Wu, Y.-L. Hsu, T.-S. Wu, K. F. Bastow,
K.-H. Lee, Org. Lett. 2006, 8, 5207 – 5210; g)B. R. Clark, R. J.
Capon, E. Lacey, S. Tennant, J. H. Gill, Org. Lett. 2006, 8, 701 –
704; h)J. C. Lee, E. Lobkovsky, N. B. Pliam, G. Strobel, J. Clardy,
J. Org. Chem. 1995, 60, 7076 – 7077; i)S. Thaisrivongs, M. N.
Janakiraman, K.-T. Chong, P. K. Tomich, L. A. Dolak, S. R.
Turner, J. W. Strohbach, J. C. Lynn, M.-M. Horng, R. R.
Hinshaw, K. D. Watenpaugh, J. Med. Chem. 1996, 39, 2400 –
2410.
[13] a)C. Nieto-Oberhuber, M. P. Muæoz, E. Buæuel, C. Nevado,
D. J. Cµrdenas, A. M. Echavarren, Angew. Chem. 2004, 116,
2456 – 2460; Angew. Chem. Int. Ed. 2004, 43, 2402 – 2406; b)C.
Nevado, D. J. Cµrdenas, A. M. Echavarren, Chem. Eur. J. 2003, 9,
2627 – 2635; c)S. López, E. Herrero-Gómez, P. PØrez-Galµn, C.
Nieto-Oberhuber, A. M. Echavarren, Angew. Chem. 2006, 118,
6175 – 6178; Angew. Chem. Int. Ed. 2006, 45, 6029 – 6032; d)C.
Nieto-Oberhuber, S. López, M. P. Muæoz, D. J. Cµrdenas, E.
Buæuel, C. Nevado, A. M. Echavarren, Angew. Chem. 2005, 117,
6302 – 6304; Angew. Chem. Int. Ed. 2005, 44, 6146 – 6148; e)N.
MØzailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133 – 4136;
f)S. I. Lee, S. M. Kim, M. R. Choi, S. Y. Kim, Y. K. Chung, W.-S.
Han, S. O. Kang, J. Org. Chem. 2006, 71, 9366 – 9372.
[14] A possible pathway for additional reaction products is:
[4] M. D. Burke, S. L. Schreiber, Angew. Chem. 2004, 116, 48 – 60;
Angew. Chem. Int. Ed. 2004, 43, 46 – 58.
[5] a)M. E. Jung, J. A. Hagenah, J. Org. Chem. 1987, 52, 1889 –
1902; b)R. K. Dieter, J. R. Fishpaugh, J. Org. Chem. 1988, 53,
2031 – 2046; c)C. J. Douglas, H. M. Sklenicka, H. C. Shen, D. S.
Mathias, S. J. Degen, G. M. Golding, C. D. Morgan, R. A. Shih,
K. L. Mueller, L. M. Scurer, E. W. Johnson, R. P. Hsung,
Tetrahedron 1999, 55, 13683 – 13696; d)S. Ma, S. Yu, S. Yin, J.
Org. Chem. 2003, 68, 8996 – 9002; e)I. Hachiya, H. Shibuya, M.
Shimizu, Tetrahedron Lett. 2003, 44, 2061 – 2063; f)S. G. Gil-
breath, C. M. Harris, T. M. Harris, J. Am. Chem. Soc. 1988, 110,
6172 – 6179.
[6] a)T. Fukuyama, Y. Higashibeppu, R. Yamaura, I. Ryu, Org.
Lett. 2007, 9, 587 – 589; b)Y. Kishimoto, I. Mitani, Synlett 2005,
2141 – 2146.
[7] a)R. Hua, M. Tanaka, New J. Chem. 2001, 25, 179 – 184; b)R. C.
Larock, M. J. Doty, X. Han, J. Org. Chem. 1999, 64, 8770 – 8779.
[8] For reviews, see: a)L. F. Tietze, Chem. Rev. 1996, 96, 115 – 136;
b)P. J. Parsons, C. S. Penkett, A. J. Shell, Chem. Rev. 1996, 96,
195 – 206; c)H. Pellissier, Tetrahedron 2006, 62, 1619 – 1665;
d)H. Pellissier, Tetrahedron 2006, 62, 2143 – 2173; e)A. Padwa,
S. K. Bur, Tetrahedron 2007, 63, 5341 – 5378.
[9] a)J. Zhao, C. O. Hughes, F. D. Toste, J. Am. Chem. Soc. 2006,
128, 7436 – 7437; b)S. Wang, L. Zhang, J. Am. Chem. Soc. 2006,
128, 8414 – 8415; c)A. W. Sromek, A. V. Kelꢀin, V. Gevorgyan,
Angew. Chem. 2004, 116, 2330 – 2332; Angew. Chem. Int. Ed.
2004, 43, 2280 – 2282; d)Y. Shigemasa, M. Yasui, S. Ohrai, M.
Sasaki, H. Sashiwa, H. Saimoto, J. Org. Chem. 1991, 56, 910 –
912; e)K. Cariou, E. Mainetti, L. Fensterbank, M. Malacria,
Tetrahedron 2004, 60, 9745 – 9755; f)M. Yu, G. Zhang, L. Zhang,
Org. Lett. 2007, 9, 2147 – 2150.
[15] a)C. Ferrer, A. M. Echavarren, Angew. Chem. 2006, 118, 1123 –
1127; Angew. Chem. Int. Ed. 2006, 45, 1105 – 1109; b)C. Ferrer,
C. H. M. Amijs, A. M. Echavarren, Chem. Eur. J. 2007, 13, 1358 –
1373; c)M. T. Reetz, K. Sommer, Eur. J. Org. Chem. 2003, 3485 –
3496; d)Z. Shi, C. He, J. Org. Chem. 2004, 69, 3669 – 3671.
[16] a)M. M. Singh, Med. Res. Rev. 2001, 21, 302 – 347; b)Y.-Q. Long,
X.-H. Jiang, R. Dayam, T. Sanchez, R. Shoemaker, S. Sei, N.
Neamati, J. Med. Chem. 2004, 47, 2561 – 2573; c)L.-W. Hsin,
C. M. Dersch, M. H. Baumann, D. Stafford, J. R. Glowa, R. B.
Rothman, A. E. Jacobson, K. C. Rice, J. Med. Chem. 2002, 45,
1321 – 1329.
[17] CCDC-650319 (3d)contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[18] a)C. Nieto-Oberhuber, S. López, A. M. Echavarren, J. Am.
Chem. Soc. 2005, 127, 6178 – 6179; b)T. J. Harrison, B. O.
Patrick, G. R. Dake, Org. Lett. 2007, 9, 367 – 370.
[10] For recent applications, see: a)L. Zhang, S. Wang, J. Am. Chem.
Soc. 2006, 128, 1442 – 1443; b)P. Y. Toullec, E. Genin, L.
Angew. Chem. Int. Ed. 2007, 46, 8250 –8253
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