Highly diastereoselective synthesis of bicyclo-[3.2.1]octenones through phosphine-mediated condensations of 1,4-dien-3-ones

Article abstract of DOI:10.1002/anie.200600126

(Chemical Equation Presented) Making rings: A highly diastereoselective synthesis of bicyclo[3.2.1]octenones from 1,4-dien-3-ones occurs through a domino phosphine-mediated formal [4+2] cycloaddition followed by an intramolecular Wittig olefination.

Full text of DOI:10.1002/anie.200600126

Angewandte
Chemie
Synthetic Methods
We began our investigations with the reaction of phos-
phines with 1,4-dien-3-ones to determine the feasibility of a
phosphine-catalyzed all-carbon [4+2] annulation (Scheme 1).
When styryl vinyl ketone (R = H) is mixed with Ph3P in THF,
DOI: 10.1002/anie.200600126
Highly Diastereoselective Synthesis of Bicyclo-
[3.2.1]octenones through Phosphine-Mediated
Condensations of 1,4-Dien-3-ones**
Nolan T. McDougal and Scott E. Schaus*
New methods for the construction of highly substituted
carbocycles with a defined configuration are important for the
synthesis of natural products and drugs.[1] The synthesis of
cyclic compounds that possess all-carbon quaternary centers
is a challenge that has been primarily addressed by the
alkylation of enolates,[2] the Diels–Alder reaction,[3] and
radical cyclizations.[4] One elegant approach is the [4+3]
cycloaddition of oxyallyl cations with substituted dienes and
furans to afford bicycles that contain quaternary carbon
centers.[5] Complementary approaches to simple carbocycles
from acyclic precursors include phosphine-mediated methods
such as [3+2] annulations[6] as well as intramolecular Rauhut–
Currier,[7] Morita–Baylis–Hillman,[8] and SN2 reactions.[9]
Despite the myriad approaches afforded by these reactions,[10]
few synthetic methods that produce quaternary carbon-
containing bicyclic structures by using nucleophilic promoters
exist.[11] Herein we report the phosphine-mediated highly
diastereoselective synthesis of bicyclo[3.2.1]octenones[12] that
bear two bridgehead quaternary carbon centers from 1,4-
dien-3-ones by a formal [4+2] cycloaddition–Wittig reaction
process.
1,4-Dien-3-ones are useful multifunctional building blocks
in the synthesis of carbocyclic compounds. A recent report
illustrated their utility in the synthesis of cyclohexenones
through an electrocyclic ring closure following base-mediated
formation of the corresponding hexatriene.[13] Intermolecular
Diels–Alder reactions[14] of 1,4-dien-3-ones as electron-defi-
cient dienophiles also afford carbocyclic structures. Cyclo-
pentenones and highly substituted bicycles are readily
accessed through another type of electrocyclic ring closure
of dienones, the Nazarov reaction.[5a–d,15] On the basis of the
multifunctional nature of 1,4-dien-3-ones, we believed that
they could serve as latent 1,3-dienes in [4+2] annulation
reactions.
Scheme 1. Phosphine-promoted reactions of 1,4-dien-3-ones.
the Rauhut–Currier product is formed in 53% yield (Path A).
Although this result confirms that the enolate can be
generated in situ, a-proton transfer leads to the Rauhut–
Currier reaction pathway. To investigate other reaction
pathways of this type of latent 1,3-diene, we synthesized a-
substituted 1,4-dien-3-ones (Path B). When styryl isopropenyl
ketone (1a) was treated with nBu3P in CH2Cl2 at room
temperature, we found that bicyclo[3.2.1]octenone 2a formed
as a single diastereomer in 15% yield (Table 1, entry 1).
Bicyclo[3.2.1]octanes are subunits of a variety of biologically
active terpenes, including the scopadulcic acids,[16] gibberel-
lins,[17] and aphidicolane diterpenes.[18] We screened various
electronically and sterically different phosphines[19] and found
that 1 equivalent of Et2PhP mediated the condensation
reaction in 65% yield after 20 h (Table 1, entry 3). Substoi-
chiometric amounts of phosphine resulted in extended
reaction times and lower yields. Although the reaction
proceeded in most polar, non-ether solvents (CHCl3, PhCF3,
Table 1: Phosphine-mediated synthesis of bicyclo[3.2.1]octenone 2a.[a]
Entry
Phosphine
Additive
Yield [%][b]
15[c]
1
2
3
4
5
6
7
8
nBu3P
Cy3P
Et2PhP
EtPh2P
Ph3P
Et2PhP
Et2PhP
Et2PhP
–
–
–
–
[*] N. T. McDougal, Prof. Dr. S. E. Schaus
Department of Chemistry
[d]
–
65
Metcalf Center for Science and Engineering
Boston University
590 Commonwealth Avenue, Boston, MA 02215 (USA)
Fax: (+1)617-353-6466
[e]
–
[e]
–
–
DBU
Et3N
pyridine
44
65
76
E-mail: seschaus@bu.edu
[**] The authors acknowledge Dr. J. P. Lee (Boston University) for
assistance with key NMR spectroscopy experiments and Dr. E. B.
Lobkovsky (Cornell University) for X-ray crystallographic analysis.
This research was supported by a NSF CAREER grant (CHE-
0349206) and Amgen, Inc.
[a] Reactions were run with ketone (0.3 mmol), phosphine (0.3 mmol),
and additive (0.3 mmol) in CH2Cl2 (0.5m) at room temperature for 20 h
under Ar, followed by flash chromatography on silica gel. [b] Yield of
isolated product. [c] Reaction time was 5 min. [d] Decomposition of 1a.
[e] No reaction observed by 1H NMR spectroscopy. Cy=cyclohexyl,
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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CH3CN), the best yields were obtained with anhy-
drous CH2Cl2. Basic additives affected the reaction
yield (Table 1, entries 6–8). The use of 1 equivalent of
pyridine improved the yield to synthetically useful
levels while maintaining the high diastereoselectivity
(Table 1, entry 8); no reaction was observed when
pyridine was used in the absence of phosphine.[20]
Therefore, we selected 1 equivalent each of Et2PhP
and pyridine in CH2Cl2 at room temperature as
general reaction conditions.
These reaction conditions proved general for a
variety of 1,4-dien-3-ones (Table 2). Halogen- and
alkyl-substituted aryl substrates 1b–d cleanly under-
went condensation in yields greater than 70%.
Heteroaromatic and electron-donating aromatic
dienones afforded the bicyclo[3.2.1]octenone prod-
ucts in good yields, although gentle heating was
reactivity of the dienones, the reaction of 1e with Et2PhP and
pyridine in the presence of a stoichiometric amount of 1n
resulted in the exclusive formation of 2e, the condensation
product of 2 equivalents of 1e. The heterodimer product,
afforded by the reaction of 1 equivalent each of 1e and 1n,
was not observed. This might have been due to the higher
electrophilicity of aromatic over aliphatic substrates toward
both the nucleophilic addition of Et2PhP and the reaction of
the resulting 1,3-diene.
We propose herein a mechanism for the condensation
reaction in which the phosphine fulfills two roles
(Scheme 2).[21] Nucleophilic addition of the phosphine to 1
affords diene 3.[22] A formal [4+2] cycloaddition of 3 with
another 1 equivalent of 1 in an endo fashion yields cyclo-
adduct 4 as one diastereomer. We postulate that pyridine
facilitates the proton transfer to protonate enolate 4 and form
phosphorus ylide 5.[23] When the reaction of 1a was conducted
in CDCl3/D2O (9:1), we observed deuterium incorporation at
the methylene a to the carbonyl group and at the cyclic-olefin
methine positions of 1b (both 82% Dincorporation),
suggesting that the protonation of 4 may occur by an
intermolecular process and that formation of 5 is reversible.
Notably, deuterium incorporation was not observed at the
bridgehead methylene or the exocyclic vinyl hydrogen atoms,
Table 2: Phosphine-mediated synthesis of bicyclo[3.2.1]octenes.[a]
Entry
R1
R2
Yield [%][b]
a
b
c
d
C6H5
4-F-C6H4
CH3
CH3
CH3
CH3
76
70
70
75
75
70
73
66
41
60
60
4-Br-C6H4
4-Me-C6H4
2-furylCH
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
C6H5
e
3
f[c]
g
CH3
CH3
CH3
CH2CH3
CH3
h[d]
i[e]
j[f]
k[f]
H3C(CH2)6
2-furyl-(CH2)2
CH3
[a] Reactions were run with ketone (0.3 mmol), pyridine (0.3 mmol), and
Et2PhP (0.3 mmol) in CH2Cl2 (0.5m) at room temperature for 20 h under
Ar, followed by flash chromatography on silica gel. [b] Yield of isolated
product. [c] Reaction time was 30 h. [d] Reaction was run at 308C.
[e] Reaction was run in CHCl3 at 508C. [f] nBu3P, added over 6 h, was
used at 08C.
required for the 4-methoxy derivative 1h (Table 2,
entries e–h). Substitutional effects were more pro-
nounced at other positions of the 1,4-dien-3-one
backbone. The condensation of 2-ethyl-1,4-dienone
1i resulted in lower yields, although heating to 508C
in CHCl3 afforded the desired product in 41% yield
after 20 h (Table 2, entry i). Substrates bearing alkyl
substituents (Table 2, entries j,k) did not react under
the general conditions; however, the use of more-
nucleophilic phosphines such as nBu3P resulted in
effective condensation of these less-electrophilic
enones to afford the bicyclic products. Dienones 1l–
n underwent condensation under similar reaction
conditions; Et2PhP was the nucleophilic promoter for
aromatic 1l and 1m [Eq. (1)], whereas geranal-
derived 1n required nBu3P for optimal yields
Scheme 2. Proposed mechanism for the phosphine-mediated synthesis of
[Eq. (2)]. In an experiment designed to explore the
bicyclo[3.2.1]octenones.
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which indicates that the [4+2] cycloaddition may not be
reversible. Finally, intramolecular Wittig olefination[24] of 5
and the a,b-unsaturated carbonyl group located on the same
face of the cyclohexanone ring afforded the bicyclo-
[3.2.1]octenone 2 and phosphine oxide, as observed by
31P NMR spectroscopy. Given this proposed mechanism, we
conducted experiments to test whether 5 could undergo
intermolecular Wittig olefinations with aldehydes in situ. The
reaction of 1a with Et2PhP in the presence of benzaldehyde,
acetaldehyde, or paraformaldehyde resulted solely in the
formation of the bicyclic product 2a. Intermolecular Wittig
olefination products were not formed, suggesting a fast
intramolecular olefin-formation step.
In summary, we have developed a highly diastereoselec-
tive phosphine-mediated synthesis of bicyclo[3.2.1]octenones
that contain two quaternary carbon centers by a domino
[4+2] cycloaddition–Wittig reaction process. The phosphine
acts as both a nucleophilic promoter to generate a 1,3-diene
and a mediator of intramolecular olefination. Experiments
designed to explore the scope and limitations of this reaction
are ongoing and will be reported in due course.
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Received: January 11, 2006
Published online: April 5, 2006
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