Gold-catalyzed three-component tandem process: An efficient and facile assembly of complex butenolides from alkynes, amines, and glyoxylic acid

Article abstract of DOI:10.1021/ja101804p

An efficient and facile gold-catalyzed three-component tandem process for the assembly of two types of highly functionalized butenolides has been developed. In this reaction system, more than four chemical bonds are formed by a single gold catalyst. The present tandem protocol includes a direct coupling of alkynes, amines, and glyoxylic acid and subsequent exclusively endo-selective cycloisomerization of alkynoic acids along with intermolecular electrophilic trapping; it utilizes three simple and commercially available starting materials to assemble architecturally complex and appealing butenolide scaffolds bearing other reactive sites for further manipulation.

Full text of DOI:10.1021/ja101804p

Published on Web 05/10/2010
Gold-Catalyzed Three-Component Tandem Process: An Efficient and Facile
Assembly of Complex Butenolides from Alkynes, Amines, and Glyoxylic Acid
Qiang Zhang,†,‡ Ming Cheng,†,‡ Xiaoyu Hu,†,‡ Bo-Gang Li,† and Jian-Xin Ji*,†
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, People’s Republic of China, and
Graduate School of the Chinese Academy of Sciences, Beijing 100039, People’s Republic of China
Received March 3, 2010; E-mail: jijx@cib.ac.cn
Table 1. Optimization Study:a Tandem Access to Butenolides
Butenolides are prevalent structural motifs in more than 13 000
natural products,1 some acting as antibiotic, antifungal, antifouling,
or anticancer agents2 as well as pharmaceuticals such as Merck’s
Rofecoxib. General and convenient methods for construction of
butenolide skeletons bearing multiple reactive sites for further func-
tionalizations are of great interest.3 Herein, we report an expeditious
entry
catalyst
reaction conditions
yield (%)b
and practical gold-catalyzed multicomponent reaction (MCR) for the
formation of polysubstituted butenolides in a tandem manner. This
MCR consists of a novel direct alkyne-amine-glyoxylic acid
coupling, intramolecular cyclization of R-N-substituted ꢀ-alkynoic acid
A, and subsequent reaction (eq 1). Copper salts, which have been
utilized extensively in aldehyde-amine-alkyne coupling,4 cannot
trigger the first step in our tandem course, indicating the exceptional
catalytic ability of gold to generate A from alkyne, amine, and glyoxylic
acid. The transformation of A to B, to the best of our knowledge, is
the first example of gold-catalyzed cyclization of alkynoic acids in
exclusive endo-dig fashion.5 The unique reactivity of the cyclization
intermediate is revealed by intermolecular electrophilic trapping, which
introduces an R-amino acid moiety and thus builds a highly congested
quaternary carbon center at the γ position in the butenolide architecture.
1
2
3
4
5
6
7
8
9
AuCl3
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
CH2Cl2, r.t., 24 h
CH2Cl2, r.t., 24 h
CH3CN, r.t., 24 h
CH3OH, r.t., 24 h
CH3OH, 50 °C, 8 h
H2O, 50 °C, 8 h
10
24
39
56
78
trace
<40
0d
AuBr3/dppfc or PPh3
CuBr, CuBr2, CuI
HBr, H3PO4, TfOH
CH3OH, 50 °C, 8 h
CH2Cl2, r.t., 24 h
CH3OH, 50 °C, 72 h
0d
a Reaction conditions: 1 (1 mmol), 2a (2 mmol), 3a (1.2 mmol).
b Isolated yields. c dppf )1,1′-bis(diphenylphosphino)ferrocene. d No A,
4a, or other product was detected.
methanol along with smooth heating (entry 5). Other solvents, such
as CH2Cl2, CH3CN, and H2O (entries 2, 3, and 6) and use of ligands
(entry 7) failed to increase the yields.
Table 2. Gold-Catalyzed Three-Component Formation of
Butenolides 4a b
,
Demands for facile and efficient generation of complex and diverse
druglike small molecules continue to stimulate the design and
development of conceptually innovative strategies in the synthetic
community. In this context, tandem processes enabling multiple bond-
forming events to occur in a one-pot manner using gold catalysts have
been elegantly demonstrated, affording structurally appealing carbo-
or heterocyclic ring systems through the remarkably reactive versatility
of gold with π bonds.6 However, most gold catalysis, in either
intramolecular or two-component style, requires preformed and
relatively complex precursors. In this communication, we illustrate a
new gold-initiated tandem pattern with prominent synthetic efficacy
from molecular simplicity to complexity, including an MCR that
combines simple and commercially available raw materials, a subse-
quent intramolecular functional-group-pairing reaction, and a secondary
MCR. Furthermore, the ability to apply a single catalyst for the above
processes could significantly enhance the operational convenience.
In the initial attempt, gold catalysts were attempted for reactions of
glyoxylic acid (1), 4-phenyl-1-butyne (2a), and morpholine (3a). AuBr3
and AuCl3 were able to catalyze the formation of butenolide 4a (Table
1, entries 1-7), while copper salts and Brønsted acids were found to
be inactive (entries 8 and 9). Apparently, the yields were improved in
a Conditions: 1 (1 mmol), 2 (2.0 mmol), 3 (1.2 mmol). b Isolated yields.
With the optimal reaction conditions in hand, the scope and
limitation of this reaction were tested with various combinations of
alkynes and amines (Table 2). For example, the terminal alkynol was
tolerated, providing a handle for subsequent orthogonal reactivity (4g).
Similarly, the aliphatic chain bearing two terminal alkyne moieties
also afforded the expected butenolides with one remaining alkyne for
further manipulation (4h). However, the aromatic alkyne phenylacety-
† Chengdu Institute of Biology.
‡ Graduate School of the Chinese Academy of Sciences.
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10.1021/ja101804p  2010 American Chemical Society

C O M M U N I C A T I O N S
lene gave product 4l in only 5% yield. The major isolated product
was butenolide 5a having a tethered an R-amino acid moiety at the γ
position. It was envisaged that the γ-carbon was trapped by iminium ion
to achieve a higher level of atom economy and molecular complexity.
After optimization of the reaction, we found that butenolide 5a could be
produced with a yield of 68% in methanol under very mild condition (25
°C). Aliphatic alkynes failed to afford butenolides similar to 5a.
acid occurs, affording R-N-substituted ꢀ-alkynoic acid A through an
addition reaction involving a gold acetylide intermediate as the
nucleophile (cycle I). Next, gold-promoted endo-dig cyclization of A
leads to the active intermediate B, which is finally transformed to
butenolides via electrophilic trapping along with a deprotonation-
protonation sequence or 1,2-hydride shift pathway.8
Scheme 1. Tentative Mechanism
To further investigate the unique reactivity of the in situ-
generated cyclization intermediate, other aromatic alkynes and
amines were used as substrates. As expected, phenylacetylene
bearing representative substituents along with either a cyclic
secondary amine (morpholine) or an acyclic amine (dibenzylamine)
could deliver the desired butenolides (Table 3). It is noteworthy
that these products represent a novel kind of unnatural R-amino
acid that could serve as a versatile building block for polypeptide
analogue research in drug discovery. The R-amino acid moieties
could also work as efficient attachment handles on the butenolide
skeleton, leading to greater diversity through further manipulation.
Table 3. Tandem Process Using Aromatic Alkynesa b
,
In summary, we have developed a gold-catalyzed three-component
tandem process for the synthesis of two new types of butenolides. This
tandem reaction consists of two catalytic processes in which more than
four chemical bonds are formed in the presence of a single gold
catalyst. In addition, two sequential carbon-carbon bond-forming
reactions are involved in the construction of butenolide skeleton B.
The present tandem protocol, which utilizes three commercially available
starting materials to assemble highly functionalized butenolides, provides
a useful synthetic method and expands the area of gold catalysis. Studies
of the detailed mechanism and its application are ongoing.
Acknowledgment. We are grateful for the financial support
from the National Science Foundation of China (20802072).
Supporting Information Available: Experimental procedures,
characterization data for new compounds, and X-ray data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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configuration of anti-5g was established by X-ray analysis and nuclear
Overhauser effect spectroscopy together with conformational analysis.7
The remaining products’ relative configurations were assigned by
analogy. Isolated yields are listed. b The diastereomeric ratios (syn:anti)
(1) This number is based on a survey of the Beilstein database.
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1
were determined by H NMR analysis (5a-f) or HPLC (5g-i).
To shed light on the reaction mechanism, attempts to isolate the
intermediate A were made. In almost all cases, the cyclization was
too rapid, and A could not be detected directly. Fortunately, compound
7 could be isolated in low yield through a fast preparative TLC method
in the initial catalytic stage, when 6c was used as the starting material.
Treatment of 7 with gold catalyst under the standard procedure allowed
the cyclization of 7 and formation of 5c (eq 2).
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(7) See the Supporting Information.
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On the basis of the above results and previous studies,5 we have
proposed the following mechanism shown in Scheme 1. First, gold-
catalyzed three-component coupling of alkyne, amine, and glyoxylic
JA101804P
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