Atom- and step-economical pathway to chiral benzobicyclo[2.2.2]octenones through carbon-carbon bond cleavage

Article abstract of DOI:10.1002/anie.201108446

In the nick of time: A nickel-catalyzed asymmetric intramolecular alkene insertion reaction into cyclobutanones (1) has been developed. The reaction significantly reduces the number of steps required for the synthesis of chiral benzobicyclo[2.2.2]octenones (2). Copyright

Full text of DOI:10.1002/anie.201108446

Angewandte
Chemie
DOI: 10.1002/anie.201108446
Homogeneous Catalysis
Atom- and Step-Economical Pathway to Chiral Benzobicyclo-
[2.2.2]octenones through Carbon–Carbon Bond Cleavage**
Lantao Liu, Naoki Ishida, and Masahiro Murakami*
It has become an imperative issue to improve the step[1] as
well as atom economy[2] of organic synthesis. A highly atom-
economical method to construct carbon frameworks could
arise if an unsaturated organic functionality is directly
inserted into a carbon–carbon single bond.[3] Such an insertion
reaction also dispenses with functional group manipulations
to significantly reduce the steps required for construction of
a particular organic skeleton.
a racemic mixture that additioanlly necessitates a resolution
process.[5] There has been no report on the straightforward
enantioselective synthesis from an achiral precursor.
We have developed a nickel-catalyzed reaction of cyclo-
butanones 4 in which an alkene undergoes intramolecular
insertion into a carbon–carbon single bond to produce
benzobicyclo[2.2.2]octenones 5 [Eq. (1)].[6] The starting cyclo-
A class of benzobicyclo[2.2.2]octene derivatives (1–3;
Figure 1)) is known to possess a variety of biological
activities.[4] For example, benzobicyclo[2.2.2]octenols 1 act
butanone can be prepared from 1,2-divinylbenzene through
[2+2] cycloaddition with dichloroketene and subsequent
reductive dechlorination. Thus, it would provide a more
step-economical access to benzobicyclo[2.2.2]octene deriva-
tives in an enantiomerically enriched form if the alkenyl
group is inserted into one of the enantiotopic carbon–carbon
single bonds of the symmetrical cyclobutanone. Herein we
describe a nickel-catalyzed asymmetric intramolecular alkene
insertion reaction of 3-(2-styryl)cyclobutanones, a reaction
that significantly reduces the steps required for the synthesis
of chiral benzobicyclo[2.2.2]octenones.
Figure 1. Biologically active benzobicyclo[2.2.2]octene derivatives.
Initially, various types of chiral ligands for nickel were
examined in the reaction of the cyclobutanone 4a (Table 1).
Whereas typical bidentate diphosphine ligands like BINAP
and DuPhos showed no catalytic activity, monodentate
phosphine ligands exhibited the potential to promote the
insertion reaction. In particular, phosphoramidite ligands
derived from binol[7] afforded promising results in terms of
both the yield and the enantioselectivity. When phosphor-
amidite 6 was used, the reaction proceeded at 1008C and 5a
was obtained in 25% yield with 5% ee (entry 1). The
phosphoramidite ligand 7, which is combined with chiral 1-
phenylethylamine, gave a better result both in the yield and
the enantioselectivity (entry 2), both of which were improved
to 66% yield and 75% ee when 8, having a more sterically
demanding 1-(1-naphthyl)ethylamine group, was used as the
amine moiety (entry 3). The diastereomer 9, incorporating
the antipode of the chiral amine of 8, gave an inferior result
(entry 4). Notably, both phosphoramidite ligands 8 and 9
afforded the same enantiomer as the major product, thus
suggesting that the axial chirality of the binol skeleton
dominated in chirality induction over the amine moieties.
Introduction of two tert-butyl groups at the 6-positions of the
binol skeleton increased the solubility of the nickel complex
in hydrocarbon solvents, thereby enhancing the catalyst
as calcium channel blockers in the treatment or prevention of
angina pectoris, ischemia, arrhythmias, high blood pressure,
and cardiac insufficiency. In their synthesis, benzobicyclo-
[2.2.2]octenones serve as the key intermediate with the
carbonyl group providing a cornerstone for further derivati-
zation. The reported method to synthesize the key inter-
mediate requires five steps starting from 1,4-benzoquinone
and 1,3-cyclohexadiene; four of the steps are used for
functional-group manipulation. After all, it affords only
[*] Dr. L. Liu, Dr. N. Ishida, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510, (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/murakami-lab/
[**] We thank Prof. Qi-Lin Zhou for valuable discussions. L.L. thanks the
Japan Society for the Promotion of Science for a Research Fellow-
ship. This work was supported in part by The Asahi Glass
Foundation and a Grant-in-Aid for Scientific Research on Innovative
Areas “Molecular Activation Directed toward Straightforward Syn-
thesis” from the Ministry of Education, Culture, Sports, Science and
Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108446.
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Table 1: Optimization of the reaction conditions.[a]
amidite ligand 10 favors the Re face over the Si face for
coordination to nickel, and thus, enantioselectivity is induced
at the sp3-carbon atom that is formed upon oxidative
cyclization.[11] The resulting tricyclic oxanickelacyclopentane
B is no longer symmetrical. In B, there are two diastereotopic
carbon–carbon bonds which are amenable to cleavage by b-
carbon elimination. The one located cis to the nickelamethyl
substituent is selectively cleaved because of the geometric
constraints, thus giving the bicyclic nickelacycle C. Reductive
elimination furnishes benzobicyclo[2.2.2]octenone 5a with
regeneration of the nickel(0) catalyst.
Various 3-(2-styryl)cyclobutanones were subjected to the
alkene insertion reaction (Table 2). o-Phenylene-type linkers
were allowed in place of a naphthylene linker to give
benzobicyclo[2.2.2]octenones 5d–j with enantioselectivities
ranging from 80 to 93% ee (entries 3–9). Both methoxy
(entries 1 and 4) and fluoro (entries 5, 6, and 8) groups were
tolerated on the aryl rings. In addition, the reaction of the 3,3-
disubstituted cyclobutanone 4j afforded the bicyclic ketone
5j bearing an all-carbon quaternary chiral center at the
benzylic position in 96% yield with 82% ee (entry 9). In
contrast, the insertion reaction failed to occur when substi-
tuted alkenyl groups were put on the phenyl ring in place of
a simple ethenyl group, probably because of steric reasons.
The obtained benzobicyclo[2.2.2]octenones would serve
as useful intermediates for the synthesis of the biologically
active molecules,[4] as mentioned above. Another demonstra-
tion of the synthetic utility of the products was given by the
Baeyer–Villiger oxidation reaction [Eq. (2)]. When 5a
Entry
Ligand
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
6
7
8
9
10
10
10
100
100
100
100
100
RT
2
2
2
2
2
4
4
25
39
66
35
95
85
80
5
13
75
50
78
86
91
5
6
7[d]
RT
[a] Reaction conditions: 4a (0.10 mmol;1.0 equiv), [Ni(cod)2]
(10 mol%), chiral ligand (12 mol%), toluene (1.0 mL). [b] Yield of
isolated product. [c] Determined by HPLC analysis using a chiral
stationary phase. [d] In n-hexane.
activity (entry 5).[8] As a result, the insertion reaction
proceeded at room temperature to afford 5a in 85% yield
with 86% ee (entry 6). Finally, 91% ee was attained when n-
hexane was used instead of toluene as the solvent (80% yield,
entry 7).
Mechanistically, the nickel-catalyzed reaction is initiated
by intramolecular oxidative cyclization between the vinyl
group and the cyclobutanone carbonyl group on nickel(0)
(Scheme 1).[9,10] This elementary step determines the stereo-
chemistry of the insertion reaction. Among the two enantio-
faces of the carbon–carbon double bond, the chiral phosphor-
(91% ee) was treated with 5 equivalents of mCPBA at room
temperature, the secondary carbon atom selectively under-
went oxidative migration with retention of the stereochem-
istry to furnish the lactone 11 in 70% yield. Subsequent
hydrolysis of 11 afforded the cis-substituted hydroxycarbox-
ylic acid 12 in 80% yield [Eq. (2)].
In conclusion, we have developed the asymmetric intra-
molecular alkene insertion reaction of 3-(2-styryl)cyclobuta-
nones catalyzed by a nickel complex bearing a binol-derived
phosphoramidite ligand. The reaction provides a unique and
straightforward access to enantiomerically enriched
benzobicyclo[2.2.2]octenones. It will significantly improve
the step as well as atom economy in the asymmetric synthesis
of a class of potent biologically active compounds derived
from benzobicyclo[2.2.2]octenones.
Experimental Section
A general procedure for the nickel-catalyzed reaction of 4a: In an N2-
filled glove-box, [Ni(cod)2] (2.75 mg, 0.010 mmol) and n-hexane
Scheme 1. Plausible mechanisms.
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Chemie
Table 2: Scope of cyclobutanones.[a]
(0.5 mL) were added to an oven-dried screw-cap vial containing
stirrer bar. Then chiral phosphoramidite ligand 10 (9.0 mg,
a
0.012 mmol) in n-hexane (0.5 mL) was added dropwise with stirring.
After 5 min, 4a (22.2 mg, 0.10 mmol) was added in one portion. After
being stirred at room temperature for 4 h, the reaction mixture was
concentrated, and the residue was purified by preparative thin-layer
chromatography on silica gel (n-hexane/ethyl acetate = 2:1) to afford
the product 5a (17.8 mg, 0.80 mmol, 80%): 1H NMR: d = 8.06 (d, J =
8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.40–
7.57 (m, 3H), 4.47 (t, J = 2.4 Hz, 1H), 3.60 (quint, J = 2.4 Hz, 1H),
2.41 (dd, J = 18.6, 2.4 Hz, 1H) 2.16–2.31 (m, 2H), 1.97–2.10 (m, 1H),
Entry
1
4
T [8C]
5
25
1.65–1.82 ppm (m, 2H), ½aꢀD ¼ + 183 (c = 0.15 in CHCl3). [(Daicel
Chiralcel OD-H, hexane/iPrOH = 95/5, flow rate = 1.0 mLminꢁ1, l =
254 nm): t1 = 11.7 min (major), t2 = 25.3 min (minor) ee = 91%].
RT
Received: November 30, 2011
Revised: December 27, 2011
Published online: January 27, 2012
2
RT
ꢁ
Keywords: asymmetric synthesis · C C cleavage ·
homogeneous catalysis · insertion reaction · nickel
.
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4
5
50
50
50
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