Synergistic Catalysis: Metal/Proton-Catalyzed Cyclization of Alkynones Toward Bicyclo[3.n.1]alkanones

Article abstract of DOI:10.1002/anie.201504964

A highly efficient and practical synergistically metal/proton-catalyzed Conia-ene reaction for the synthesis of bicyclo[3.n.1]alkanones has been developed. This synergistic catalysis was successfully utilized in modifying natural compounds such as methyl dihydrojasmonate, α,β-thujone, and 5α-cholestan-3-one. Furthermore, the bridged carbonyl group of bicyclo[3.2.1]alkanones could be easily attacked by nucleophiles to give the ring-opened cycloheptenone products or bicyclo[4.2.1]amide in excellent yields. These reactions provide rapid access to a diverse range of cyclic structures from simple starting materials or naturally occurring compounds. A highly efficient and practical synergistically metal/proton-catalyzed Conia-ene reaction for the synthesis of bicyclo[3.n.1]alkanones has been developed. The reaction was successfully utilized in modifying natural compounds such as methyl dihydrojasmonate, α,β-thujone, and 5α-cholestan-3-one. Furthermore, the bicyclo[3.2.1]alkanones can be ring-opened by nucleophiles to give the corresponding products in excellent yields.

Full text of DOI:10.1002/anie.201504964

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International Edition: DOI: 10.1002/anie.201504964
German Edition: DOI: 10.1002/ange.201504964
Synergistic Catalysis
Synergistic Catalysis: Metal/Proton-Catalyzed Cyclization of
Alkynones Toward Bicyclo[3.n.1]alkanones**
Shifa Zhu,* Qiaohui Zhang, Kai Chen, and Huanfeng Jiang
Abstract: A highly efficient and practical synergistically metal/
proton-catalyzed Conia–ene reaction for the synthesis of
bicyclo[3.n.1]alkanones has been developed. This synergistic
catalysis was successfully utilized in modifying natural com-
pounds such as methyl dihydrojasmonate, a,b-thujone, and 5a-
cholestan-3-one. Furthermore, the bridged carbonyl group of
bicyclo[3.2.1]alkanones could be easily attacked by nucleo-
philes to give the ring-opened cycloheptenone products or
bicyclo[4.2.1]amide in excellent yields. These reactions provide
rapid access to a diverse range of cyclic structures from simple
starting materials or naturally occurring compounds.
b-caryolanol,[5] taxol,[6] and hypoestoxide[7] (Scheme 1).
Among them, taxol is the most notable molecule, which
contains the bicyclo[5.3.1] system and shows potent antitumor
activity. It is a commercial drug used to treat many types of
cancer including ovarian cancer, breast cancer, lung cancer,
and pancreatic cancer.[6]
S
ynergistic catalysis is a powerful synthetic strategy both in
nature and in the laboratory.[1] It is a specialized approach to
catalysis whereby at least two different catalysts act on two
different reactive sites simultaneously to facilitate chemical
reactions (Figure 1).[1c]
The highly strained bicyclo[3.n.1] system is the core
structure of many important naturally occurring and biolog-
ically active substances[2] such as enaimeone A,[3] garcinol,[4]
Scheme 1. Bioactive or natural compounds bearing bicyclo[3.n.1] sys-
tems.
Owing to the promising biological properties and chal-
lenging structures of these bicyclic molecules, considerable
research efforts have been devoted to develop efficient
methods to construct these carbon-bridged medium-sized
rings.[2,8] Traditionally, the bicyclo[3.n.1] systems were con-
structed through radical cyclization [Scheme 2, Eq. (1)][9] or
cationic cyclization [Eq. (2)].[10] These methods generally
suffered from low selectivities or inaccessibility of sub-
strates.[9,10] Therefore, methods for the selective synthesis of
bicyclo[3.n.1] systems would be of great importance.
Figure 1. Synergistic catalysis.
The Conia–ene reaction is an intramolecular, thermal or
Lewis-acid-catalyzed reaction of unsaturated carbonyl com-
[*] Prof. Dr. S. Zhu, Q. Zhang, K. Chen, Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (P.R. China)
E-mail: zhusf@scut.edu.cn
[**] This work was supported by the National Basic Research Program of
China (973 Program) (2011CB808600), the National Natural
Science Foundation of China (21172077, 21372086, and 21422204),
Guangdong Natural Science Foundation (2014A030313229 and
10351064101000000), SRF for ROCS, State Education Ministry, and
the Fundamental Research Funds for the Central Universities, SCUT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504964.
Scheme 2. Synthesis of bicyclo[3.n.1] systems.
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Table 1: Optimization of reaction conditions.[a]
pounds to yield cyclized products.[11] In the Conia–ene
reaction, the enolization of the ketone is the prerequisite
for cyclization. The strong enolic character of the unsaturated
b-ketoesters and b-diketones enables reactions to proceed at
low temperature [Scheme 3, Eq. (3)].[11b–f] However, mono-
ketone substrates required much harsher conditions with
reaction temperatures higher than 2508C [Eq. (4)].[11a] We
envisaged that if cyclic alkynone 1 was applied as the
substrate, a Conia–ene cyclization process might be expected
under certain catalytic conditions. Such strategy would
provide rapid access to the highly strained bicyclo-
[3.n.1]alkanone 2 [Eq. (5)].
Entry
Cat. 1
Cat. 2
Yield[b]
(5.0 mol%)
(5.0 mol%)
1
2
3
4
5
6
7
8
IMesAuCl/AgNTf2
AgOTf
AgSbF6
AgNTf2
Cu(OTf)2
In(OTf)3
Fe(OTf)3
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
IMesAuCl/AgNTf2
AgOTf
AgSbF6
Cu(OTf)2
In(OTf)3
Fe(OTf)3
–
–
–
–
–
–
–
–
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
trace
trace
97%
n.r.
n.r.
n.r.
64%
93%
89%
90%
28%
63%
n.r.
TsOH
CF3COOH
TfOH
HCOOH
HCl
B(OH)3
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TsOH
CF3COOH
HCOOH
HCl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
–
–
–
–
n.r.
n.r.
n.r.
n.r.
–
B(OH)3
n.r.
Scheme 3. Conia–ene reactions.
[a] Reaction conditions: 1a (0.25 mmol), cat. 1 (5.0 mol%), cat. 2
(5.0 mol%), solvent (1.0 mL), rt; [b] Yield of the isolated product.
IMes=1,3-dimesitylimidazol-2-ylidene; n.r. =no reaction.
With this in mind, alkyne dione (1a) was chosen as the
model substrate for this investigation. As shown in Table 1,
the reaction was conducted in DCE at room temperature with
5 mol% metal salt as the catalyst. Gold(I) was initially
applied as the catalyst because it has been shown to be a good
promoter for the Conia–ene reaction.[11b] However, the
desired bicyclo[3.2.1]alkanone product 2a was not detected
(entry 1). Other metal salts, like Ag+, Cu2+, In3+, Fe3+, were
also inefficient for this transformation (entries 2–7). As
pointed out above, the enolization of the ketone is the
prerequisite for the Conia–ene cyclization. We reasoned that
metal salts alone were not capable of enolizing the ketone,
thus the consequent cyclization did not occur. Proton (H+) is
the simplest, and arguably the most versatile, catalyst for
organic reactions, mediating an extraordinary range of
biological and synthetic transformations, including the eno-
lization of aldehydes or ketones.[1a,12] Inspired by these facts,
we turned our attention to metal/proton synergistic catalysis,
in which the metal (cat. 1) activates the carbon–carbon triple
bond and the proton (cat. 2) promotes the enolization of the
ketone. With AgNTf2 being cat. 1, a series of different
Brønsted acids (cat. 2) were then investigated (entries 8–13).
When TsOH and CF3COOH were added into the reaction
system, a trace amount of the desired bicyclo[3.2.1]alkanone
product 2a could be observed (entries 8–9). Encouraged by
this observation, a stronger Brønsted acid, TfOH, was then
employed as the co-catalyst. Gratifyingly, the product 2a
could be obtained in almost quantitative yield (entry 10).
Other acids, such as HCOOH, HCl, and B(OH)3 were
inefficient (entries 11–13). In addition to AgNTf2/TfOH,
other metal/TfOH combinations could also catalyze this
transformation, with the yields ranging from 28% to 93%
(entries 14–19). Among these metal salts, both silver and
copper salts functioned equally well, giving yields of around
90% (entries 15–17). Inferior results were obtained for the
combinations of IMes-Au+/TfOH and Fe(OTf)3/TfOH, with
the yields dropping to 64% and 63%, respectively (entries 14
and 19). However, the yield was only 28% when In(OTf)3/
TfOH was utilized as the catalyst system (entry 18). The
control reactions indicate that it is a synergistic catalysis
process, as the Brønsted acid (cat. 2) alone could not catalyze
the reaction (entries 20–25). The structure of bicyclo-
[3.2.1]alkanone 2a was confirmed by X-ray diffraction
analysis (see the Supporting Information).[13]
In light of the results in Table 1, the combination of
AgNTf2/TfOH in DCE at room temperature was then chosen
as the optimal catalyst system to study the scope of this new
transformation (Table 2). First, the reaction could be repeated
in gram scale and gave the product 2a in similar yield (96%).
Second, the catalytic system could be successfully applied to
a variety of alkynones 1. For example, in addition to 2-methyl-
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Table 2: Substrate scope.[a]
nones provided the corresponding bicyclo[3.n.1]alkanones
(n = 3, 4, 5) 2p–v in 61–90% yields. Notably, the macrocyclic
cyclododecanone-based alkynone could also be readily con-
verted to the bicyclo[9.3.1]alkanone, leading to the products
2w and 2w’ in 24% and 65% yield, respectively. A shift of the
position of the carbon–carbon double bond is observed under
acidic conditions. Actually, 2w can be fully converted into 2w’
when prolonging the reaction time to 48 h.
To demonstrate the applications of this methodology, the
synergistically metal/proton-catalyzed Conia-ene reactions
were then employed to modify the natural compounds methyl
dihydrojasmonate and a,b-thujone, which contain a five-
membered cyclic ketone moiety. Methyl dihydrojasmonate is
a diffusive aroma compound, with the smell vaguely similar to
jasmine.[15] Cyclopentanone-based alkynone 3 could be easily
obtained from the commercial available methyl dihydrojasm-
onate through known procedures. Under the standard reac-
tion conditions, the desired bicyclo[3.2.1]alkanone 4 was
furnished in 63% yield (Scheme 4). Similarly, a,b-thujone can
also be readily converted to alkynone 5, which was then
treated with AgNTf2/TfOH leading to the desired bicyclo-
[3.2.1]alkanone 6 in 60% yield. It should be noted that only
one isomer of 6 was observed (Scheme 4).
[a] 1 (0.25 mmol), AgNTf2 (5.0 mol%), TfOH (5.0 mol%), DCE (1.0 mL),
rt, 12 h; [b] 1a (6.7 mmol, 1.5 g); [c] 508C, 12 h.
2-phenylpropynyl cyclopentadione 1a, various cyclopenta-
dione-based alkyne dione derivatives with different R1 and R2
groups could be effectively converted to the desired bicyclo-
[3.2.1]alkanones (2b–n).[14] With different R1 groups on the
cyclopentadione ring, the yields were 83–98% (2b–e). The
aryl substituents at R2 have little effect on the yields (2 f–j, 80–
99%). Furthermore, the reactions smoothly occurred even for
alkynones with free hydroxy or acetamido groups, albeit in
lower yields (2k–l). Moreover, when the reaction temper-
ature was enhanced to 508C, the reaction could be extended
to the alkynones with one more alkenyl or alkynyl group, the
yields were 42% (2m) and 40% (2n), respectively. In
addition to the cyclopentadione-based alkyne dione deriva-
tives, the cycloalkanones with only one carbonyl on the ring
were also good substrates for this transformation (2o–w). For
example, 2-phenylpropynyl-cyclopentanone gave 2o in 55%
yield. Having established the synergistic catalysis as a reliable
and efficient process to construct bicyclo[3.2.1]alkanones, we
then proceeded to explore the synthesis of other bicyclo-
[3.n.1]alkanones. A series of alkynones with different ring
sizes of the alkynones 1 were then tested under the reaction
conditions and found to work well. For example, cyclo-
hexanone-, cycloheptanone-, and cyclooctanone-based alky-
Scheme 4. Modification of methyl dihydrojasmonate and a,b-thujone:
a) ketone (1.0 equiv), propargyl bromide (1.0 equiv), LDA (1.0 equiv),
THF, À788C–rt, 12 h; b) ArI (1.5 equiv), PdCl2(PPh3)2 (10 mol%), CuI
(20 mol%), NEt3 (1.5 equiv), THF, 408C 12 h; c) AgNTf2 (5 mol%),
TfOH (5 mol%), DCE, rt, 12 h. DCE=dichloroethane; LDA=lithium-
diisopropylamide; Tf=trifluoromethanesulfonate.
To further demonstrate the synthetic utility of this
synergistic catalytic method, the structure modification was
also applied to the steroid 5a-cholestan-3-one. As shown in
Scheme 5, 5a-cholestan-3-one was initially converted to the
steroid-based alkynones 8 in good yields, which were then
subjected to the standard catalytic conditions affording
the desired bicyclo[3.3.1]alkanones
(Scheme 5).
9 in 52–68% yield
With the bicyclo[3.n.1]alkanones 2 in hand, it is speculated
=
that the bridged C O group would exhibit higher electro-
[16]
=
philicity than nonbridged C O group toward nucleophiles.
Thus, a ring-opening reaction would occur accordingly to give
the cycloheptane derivatives. For example, when bicyclo-
[3.2.1]alkanones 2a, 2 f, 2g, 2h, and 2i were treated with
MeONa, the desired cycloheptenones 10a, 10 f, 10g, 10h, and
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Experimental Section
General procedure for the synthesis of bicyclo[3.n.1]alkanones 2: To
a stirred solution of DCE (1.0 mL) at room temperature was added
1
(0.25 mmol), AgNTf2 (0.0125 mmol, 5 mol%) and HOTf
(0.0125 mmol, 5 mol%). The reaction mixture was stirred at room
temperature for 12 h. The solvent was evaporated and the residue was
purified by flash column chromatography (silica gel, mixture of
hexane/ethyl acetate).
Keywords: bicyclo[3.n.1]alkanones · Conia–ene reaction ·
cycloheptanone · enolization · synergistic catalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9414–9418
Angew. Chem. 2015, 127, 9546–9550
Scheme 5. Modification of 5a-cholestan-3-one: a) dimethyl carbonate
(3.1 equiv), NaH (2.5 equiv), KH (0.28 equiv), THF, 608C, 0.5 h;
b) ketone (1.0 equiv), propargyl bromide (2.0 equiv), Cs2CO3
(1.5 equiv), acetone, 508C, 12 h; c) ArI (1.5 equiv), PdCl2(PPh3)2
(10 mol%), CuI (20 mol%), NEt3 (1.5 equiv), THF, rt, 12 h; d) AgNTf2
(5 mol%), TfOH (5 mol%), DCE, rt (9a and 9c) or 508C (9b), 24 h.
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In summary, a highly efficient and practical synergistically
metal/proton-catalyzed Conia–ene reaction for the synthesis
of bicyclo[3.n.1]alkanones (n = 2–9) was developed. Impor-
tantly, this synergistic catalysis was successfully utilized for
modifying natural compounds bearing the cyclic ketone units,
such as methyl dihydrojasmonate, a,b-thujone, and 5a-
cholestan-3-one. Furthermore, the bridged carbonyl group
of bicyclo[3.2.1]alkanones 2 could be easily attacked by
nucleophiles to give the ring-opened cycloheptenone prod-
ucts 10 or bicyclo[4.2.1]amide 11 in excellent yields. These
reactions provide rapid access to a diverse range of cyclic
structures from simple starting materials or naturally occur-
ring compounds. Owing to the excellent substrate scope and
mild reaction conditions, this synergistic catalyst system holds
considerable potential for the construction of complex
molecules. Investigations on the asymmetric version,
a detailed reaction mechanism, and additional applications
of this reaction are underway in our laboratory.
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Received: June 1, 2015
Revised: June 13, 2015
Published online: July 3, 2015
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