One-pot Diels-Alder cycloaddition/gold(I)-catalyzed 6-endo-dig cyclization for the synthesis of the complex bicyclo[3.3.1]alkenone framework

Article abstract of DOI:10.3762/bjoc.7.114

The rapid synthesis of bicyclo[m.n.1]alkanone cores possessing quaternary carbon centers adjacent to a bridged ketone represents a significant synthetic challenge. This type of architectural feature is embedded in various complex biologically active compounds such as hyperforin and garsubellin A. Herein we report a highly diastereoselective one-pot Diels-Alder reaction/Au(I)-catalyzed carbocyclization to generate bicyclo[3.3.1]alkanones in yields ranging from 48-93%.

Full text of DOI:10.3762/bjoc.7.114

One-pot Diels–Alder cycloaddition/gold(I)-catalyzed
6-endo-dig cyclization for the synthesis of the
complex bicyclo[3.3.1]alkenone framework
Boubacar Sow, Gabriel Bellavance, Francis Barabé and Louis Barriault*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1007–1013.
Department of Chemistry, 10 Marie Curie, University of Ottawa,
Ottawa, Canada, K1N 6N5
doi:10.3762/bjoc.7.114
Received: 12 May 2011
Accepted: 30 June 2011
Published: 22 July 2011
Email:
Louis Barriault* - lbarriau@uottawa.ca
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis".
§ Phone: 1-613-562-5800; Fax 1-613-562-5170
Keywords:
Guest Editor: F. D. Toste
bicyclo[3.3.1]nonenone; carbocyclization; Diels–Alder; gold catalysis;
one-pot process
© 2011 Sow et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The rapid synthesis of bicyclo[m.n.1]alkanone cores possessing quaternary carbon centers adjacent to a bridged ketone represents a
significant synthetic challenge. This type of architectural feature is embedded in various complex biologically active compounds
such as hyperforin and garsubellin A. Herein, we report a highly diastereoselective one-pot Diels–Alder reaction/Au(I)-catalyzed
carbocyclization to generate bicyclo[3.3.1]alkanones in yields ranging from 48–93%.
Introduction
Highly oxygenated and densely substituted carbon-bridged potential has drawn attention from several research groups
medium sized rings such as 1 are commonly found in nature as [9-12].
structural frameworks of many important bioactive natural
products, and in particular, polycyclic polyprenylated In 2009, we reported a mild and highly efficient method to
acetylphloroglucinols (PPAPs) (Figure 1) [1]. In the past generate carbon-bridged frameworks of various sizes through a
decades, more than 100 PPAPs exhibiting a wide variety of gold(I)-catalyzed carbocyclization [13]. Although the cycliza-
biological activities (antibiotic, anti-HIV, anti-oxidant, etc.) tion of enol ether 5 can produce 5-exo and 6-endo products, we
have been isolated from Guttiferrea plants such as hyperforin found that gold complexes 6, having bulky phosphine ligands
(2) [2-6] and garsubellin A (3) [7,8]. The challenging synthesis such as 2-bis(tert-butylphosphino)biphenyl, gave exclusively
of PPAP structures combined with their promising therapeutic the 6-endo-dig cyclized products 7 (Scheme 1). In the course of
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Beilstein J. Org. Chem. 2011, 7, 1007–1013.
Scheme 1: Gold(I)-catalyzed 6-endo-dig cyclization.
Results and Discussion
The synthesis began by a C-alkylation of enone 8 [23] using
LDA and MeI to give the corresponding ketone in 90% yield
(Scheme 2). A second alkylation to add the propargyl chain was
carried out using LDA and propargyl bromide to afford 9 in
62% yield as an inseparable mixture of diastereomers (dr = 3:1).
Subsequently, conjugate addition of methylmagnesium bro-
mide in the presence of a catalytic amount of CuI provided the
corresponding ketone in 53% yield. The ketone was then treated
Figure 1: Structures of naturally occurring PPAPs.
our studies directed towards the synthesis of naturally occur- with TBSCl, NaI and triethylamine to give the desired
ring PPAPs and related carbon-bridged ketone scaffolds, we silylenol ether 10 in 46% yield, which upon exposure to the
envisioned that PPAP framework 1 could be generated via a Au(I) complex 6 (2 mol %) provided the desired
Au(I)-catalyzed cyclization [14-22].
bicyclo[3.3.1]nonenone 11 in 88% yield. It is important to note
Scheme 2: Synthesis of papuaforin A core 4.
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Beilstein J. Org. Chem. 2011, 7, 1007–1013.
Scheme 3: Proposed domino Diels–Alder reaction/gold(I)-catalyzed cyclization.
that the Au(I)-catalyzed cyclization proceeds in high yields in a ketone 15. The attractive feature of this process resides in the
sterically congested environment. The synthesis of the core of ability to generate four new stereogenic centers and three new
papuaforin (11) was achieved in five steps from enone 8.
C–C bonds in one single operation.
However, one might recognize that the low chemical yields en- To validate the above hypothesis, diene 16 (Z-isomer) was
countered in some steps undermine the efficacy of the Au(I)- heated with N-phenylmaleimide in toluene at 150 °C, for two
catalyzed cyclization approach. In order to solve this issue, we hours, by microwave irradiation (Scheme 4) (see Supporting
assumed that bicyclo[3.3.1]nonenone scaffolds can be directly Information File 1 for experimental procedures). The solution
obtained through an intermolecular Diels–Alder reaction/Au(I)- containing the Diels–Alder adduct 17 was cooled down to room
catalyzed 6-endo-dig carbocyclization (Scheme 3). Cycloadd- temperature and 2 mol % of Au(I) complex 6 was added. The
ition between diene 12 and dienophile 13 should provide the bridgedhead ketone 18 was obtained in 80% yield as a single
endo cycloadduct 14, which, in the presence of a gold(I) cata- diastereomer. The relative stereochemistry of 18 was unambigu-
lyst, would form the gold complex A. This undergoes a carbo- ously established by X-ray analysis (see Supporting Informa-
cyclization of enol ether [24-31] to afford intermediate B, which tion File 2). With this result in hand, we explored the scope of
after proto-deauration and hydrolysis affords the bridgehead this sequential reaction (Table 1).
Scheme 4: One-pot Diels–Alder cycloaddition/gold(I) catalyzed carbocyclization.
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Beilstein J. Org. Chem. 2011, 7, 1007–1013.
Table 1: Results of the one-pot Diels–Alder reaction/Au(I)-catalyzed cyclization.
entry
diene
dienophile
product (yield)a
1
(93%)
(51%)
(88%)
2
3
4
19
20
(50%)
5
(81%)
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Beilstein J. Org. Chem. 2011, 7, 1007–1013.
Table 1: Results of the one-pot Diels–Alder reaction/Au(I)-catalyzed cyclization. (continued)
6
21
(78%)
7
(77%)
8
22
(48%)
9
(56%)
aIsolated yield and dr > 25:1 in all cases.
One-pot cycloaddition/cyclization of dienes 19 and 20 (Z/E = nyl group at C2, can be stereoselectively transformed into the
6:1 ca.) with N-phenylmaleimide gave ketones 24 and 26 in 93 desired bridgehead ketones 30 and 31 in 77 and 48% yields, res-
and 88% yield, respectively, as the sole diastereomers (Table 1, pectively. Interestingly, hemiketal 32 was isolated in 56% yield,
entries 1 and 3). The use of maleic anhydride as the dienophile which suggests that the MOM group was cleaved during the
also provided the desired products 25 and 27, albeit in lower Au(I)-catalyzed carbocyclization. It is important to note that the
yields of 51 and 50%, respectively (Table 1, entries 2 and 4). E-isomer of dienes 19–23 (minor compound) do not react with
Prenylated diene 21 was smoothly converted to ketones 28 and the dienophiles, but rather isomerized to the Z-form under the
29 in 81 and 78% yield, respectively (Table 1, entries 5 and 6). reaction conditions, thus, ensuring the formation of a single
Table 1, entries 7 and 8 reveal that the diene 22, bearing a phe- diastereomer.
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Beilstein J. Org. Chem. 2011, 7, 1007–1013.
Table 2: One-pot Diels–Alder cycloaddition/Au(I)-catalyzed carbocyclization of internal alkynes.
entry
substituent R1
product
yield (%)a
1
68
2
91
74
79
3
4
aIsolated yield and dr >25:1 in all cases.
To extend the scope of the reaction, other dienes possessing Conclusion
internal alkynes were also investigated (Table 2). It can be seen In summary, we have developed an efficient stereoselective
that large substituents at the alkyne terminal position did not method for the construction of bicyclic[3.3.1]nonenone frame-
affect the efficacy of the reaction. Intermolecular cycloaddition/ works. This one-pot Diels–Alder/Au(I)-catalyzed carbocycliza-
Au(I)-catalyzed cyclization of aryl acetylene dienes 33–35 tion process provides access to synthetically useful motifs that
provided the desired ketones 37–39 in yields ranging from 68 to are found in numerous naturally occurring PPAPs. In addition,
91% (Table 2, entries 1–3). Remarkably, enyne 36 was the Au(I)-catalyzed cyclization proved to be tolerant of a steri-
converted to 40 in 79% yield (Table 2, entry 4).
cally crowded environment. Further studies to develop an
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Supporting Information
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Acknowledgements
We thank the Natural Science and Engineering Research
Council of Canada (NSERC), Merck Research Laboratories,
Merck Frosst Canada, Boehringer Ingelheim (Laval), PREA,
Canada Foundation for Innovation, Ontario Innovation Trust
and the University of Ottawa for generous funding. F.B. thanks
NSERC for post-graduate scholarship (CGS-D1).
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