Stereoselective phosphine-catalyzed synthesis of highly functionalized diquinanes

Article abstract of DOI:10.1002/anie.200905125

(Figure Presented) Two rings to rule them all: A versatile method has been developed for the room-temperature synthesis of diquinanes from acyclic precursors, thereby generating two rings, three stereocenters, and a double bond with high selectivity. The products of the double cyclization can be derivatized with excellent diastereoselection into an array of highly functionalized compounds.

Full text of DOI:10.1002/anie.200905125

Angewandte
Chemie
DOI: 10.1002/anie.200905125
Homogeneous Catalysis
Stereoselective Phosphine-Catalyzed Synthesis of Highly
Functionalized Diquinanes**
Jonathan E. Wilson, Jianwei Sun, and Gregory C. Fu*
In 2003, Tomika and co-workers reported an intriguing
PnBu3-catalyzed diastereoselective cyclization of certain
yne-diones to form bicyclic furanones with two new stereo-
centers (Figure 1).[1] They proposed that conjugate addition of
manifold (that is, conjugate-addition/cross-tautomerization to
generate a dipolar intermediate such as A). Herein, we
exploit this reactivity to achieve the phosphine-catalyzed
diastereoselective transformations of acyclic precursors into
highly functionalized diquinanes that bear multiple (three or
four) contiguous stereocenters [Reaction (1)].[3]
Not only are diquinanes (including bicyclo[3.3.0]octan-2-
ones) subunits of a wide array of bioactive compounds, but
they are also versatile intermediates in organic synthesis.[4,5]
We envisioned that a phosphine-catalyzed method for the
generation of such structures might be viable (Krische et al.
Figure 1. The phosphine-catalyzed reaction of yne-diones to form
bicyclic furanones (for simplicity, the steps are drawn as being
irreversible).
have also developed
a powerful phosphine-catalyzed
approach to the synthesis of diquinanes[6]) if a zwitterion
derived from 1 (analogous to A in Figure 1) could be induced
to undergo an intramolecular Michael addition rather than an
aldol reaction. Unfortunately, when subjected to the condi-
tions developed by Tomita et al., compound 1 was only
transformed into the target diquinane in very low yield
[<10%; Reaction (2)].
the phosphine to the alkyne is followed by tautomerization,
which furnishes zwitterionic enolate A. Next, an intramolec-
ular aldol reaction provides B, and then a second conjugate
addition generates bicycle C (the conversion of A into C by a
concerted cycloaddition may also be considered). Tautom-
erization and then elimination of the phosphine affords the
bicyclic furanone. The investigation by Tomita et al. focused
1
À
mainly on symmetrical substrates (R = C ꢀ CR), although
they did report reactions of two unsymmetrical yne-diones
which cyclized in relatively modest yield (41–50%).
The study by Tomita et al.[1] provided an excellent
illustration of how the use of a nucleophilic catalyst can
open the door to new modes of reactivity.[2] Surprisingly, to
the best of our knowledge, there have been no subsequent
investigations that further develop this interesting reaction
Upon investigating a variety of reaction parameters, such
as catalyst, temperature, solvent, and concentration, we found
that the desired reaction manifold could be obtained through
an appropriate choice of solvent and concentration. Thus, by
conducting the cyclization in CH2Cl2/EtOAc (9:1) under
more dilute conditions, we can efficiently generate the target
diquinane, which bears three new contiguous stereocenters
and an E double bond, as a single diastereomer [89% yield;
Reaction (2)].[7]
[*] Dr. J. E. Wilson, Dr. J. Sun, Prof. Dr. G. C. Fu
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] This work has been supported by the National Institutes of Health
(National Institute of General Medical Sciences, R01-GM57034),
Merck Research Laboratories, Novartis, and Boehringer Ingelheim.
We thank Evonik for a gift of phosphepine 3 and Dr. Jeffrey H.
Simpson (MIT) for assistance with NMR studies.
This phosphine-catalyzed reaction can be applied to the
stereoselective synthesis of an array of diquinanes; in each
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905125.
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Communications
Table 1: The stereoselective phosphine-catalyzed synthesis of highly functionalized diquinanes at room temperature (20% PnBu3, CH2Cl2/EtOAc).
Entry
Substrate
Product
Yield [%][a]
1
2
R=Ph
89
83
3
cyclohex-1-enyl
Cy
84
45
4[b]
5
R=Ph
88
6
7
8
9
cyclohex-1-enyl
Cy
nBu
Me
88
74
77
56
10
R=Ph
88
54
11
n-pentyl
[a] Yield of purified product (average of two experiments). All diastereomeric ratios are >20:1. [b] 1.0 equivalents of PnBu3 were used.
case, a single diastereomer is produced (Table 1).[8] For
example, the alkyne subunit can be furnished with an
aromatic, alkenyl, or alkyl group (R, Table 1); the ability to
achieve cyclizations of alkyl-substituted compounds (Table 1,
entries 4,7,8, and 11) is noteworthy, as b-alkyl-substituted
ynones are susceptible to phosphine-catalyzed isomerization
to conjugated dienones.[9] The linker between the ynone and
the enoate can bear substituents (e.g. Table 1, entries 5–9) or
even include an aromatic ring (Table 1, entries 10 and 11).
Furthermore, an existing stereocenter can control the stereo-
chemistry of the three newly created stereocenters [Reac-
tion (3)].
We are developing an enantioselective variant of this
phosphine-catalyzed diquinane synthesis. We anticipated that
this might be comparatively challenging, owing to issues such
as the potential generation of mixtures of E/Z isomers in key
intermediates and the distance between the phosphine
subunit and the site(s) of carbon–carbon bond formation. In
view of such complications, we were pleased to find that
phosphepine 3 can catalyze the synthesis of a diquinane with
promising enantioselectivity [60% ee; Reaction (7)].[11–13]
The diquinanes produced using this phosphine-catalyzed
double-cyclization process can be functionalized with a high
degree of stereoselectivity. Thus, new stereocenters can be
introduced on the a or b positions of the enone [Reaction (4)
and Reaction (5)],[10] as well as on the carbonyl group itself
[Reaction (6)].
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We have begun to explore the application of this
procedure to the synthesis of other classes of fused carbo-
cycles. Hydrindanes are an important family of targets,[14] and
in a preliminary study we have found that, without further
optimization, the procedure that we developed for the
formation of diquinanes can be employed for the generation
of 6,5 ring systems in promising yields and excellent
stereoselectivities [Reaction (8) and Reaction (9)].
Keywords: asymmetric synthesis · cyclization ·
homogeneous catalysis · organocatalysis · phosphines
.
[1] H. Kuroda, I. Tomita, T. Endo, Org. Lett. 2003, 5, 129 – 131.
[2] For reviews and leading references to nucleophilic catalysis by
phosphines, see: a) J. L. Methot, W. R. Roush, Adv. Synth. Catal.
2004, 346, 1035 – 1050; b) L.-W. Ye, J. Zhou, Y. Tang, Chem. Soc.
Rev. 2008, 37, 1140 – 1152; c) X. Lu, C. Zhang, Z. Xu, Acc. Chem.
Res. 2001, 34, 535 – 544.
[3] For earlier studies within the group of nucleophilic catalysis by
phosphines, see: a) R. P. Wurz, G. C. Fu, J. Am. Chem. Soc. 2005,
127, 12234 – 12235; b) J. E. Wilson, G. C. Fu, Angew. Chem. 2006,
118, 1454 – 1457; Angew. Chem. Int. Ed. 2006, 45, 1426 – 1429;
c) Y. K. Chung, G. C. Fu, Angew. Chem. 2009, 121, 2259 – 2261;
Angew. Chem. Int. Ed. 2009, 48, 2225 – 2227; d) S. W. Smith,
G. C. Fu, J. Am. Chem. Soc. 2009, 131, 14231 – 14233.
[4] For reviews that include leading references to the synthesis of
diquinanes, as well as examples of natural products that include a
bicyclo[3.3.0]octan-2-one ring system, see: a) G. Mehta, A.
Srikrishna, Chem. Rev. 1997, 97, 671 – 719; b) V. Singh, B.
Thomas, Tetrahedron 1998, 54, 3647 – 3692.
[5] For examples of the use of bicyclo[3.3.0]octan-2-ones as
intermediates in natural product synthesis, see: a) A. Wrobleski,
K. Sahasrabudhe, J. Aubꢀ, J. Am. Chem. Soc. 2002, 124, 9974 –
9975; b) J. D. Winkler, M. B. Rouse, M. F. Greaney, S. J.
Harrison, Y. T. Jeon, J. Am. Chem. Soc. 2002, 124, 9726 – 9728;
c) J. Yang, Y. O. Long, L. A. Paquette, J. Am. Chem. Soc. 2003,
125, 1567 – 1574.
[6] J.-C. Wang, S.-S. Ng, M. J. Krische, J. Am. Chem. Soc. 2003, 125,
3682 – 3683. This method proceeds best at 1108C and is not
effective for the synthesis of hydrindanes (“dramatically reduced
diastereoselectivities and yields”).
[7] At higher concentrations, intermolecular processes appear to
predominate; other solvents (e.g., Et2O, toluene, and chloro-
form) and other potential catalysts (e.g., PMe3, PCy3, P(anisyl)3,
and NEt3) are less effective.
[8] Under our standard conditions, formation of the desired
diquinane is not observed when R = H or Si(tBu)Me2 (Table 1)
or when the ester is replaced with a ketone. According to
31P NMR spectroscopy, the free phosphine, not a phosphonium-
ion intermediate, is the resting state of the catalyst during the
diquinane-forming process.
In summary, building on a powerful but largely unex-
ploited mode of reactivity discovered by Tomita et al.[1]
(phosphine catalysis by initial conjugate addition followed
by cross-tautomerization of an unsaturated carbonyl com-
pound), we have developed a versatile new method for the
room-temperature synthesis of diquinanes from acyclic pre-
cursors, thereby generating two rings, three stereocenters, and
a double bond with high selectivity. The products of the
double cyclization can be derivatized with excellent diaster-
eoselection into an array of highly functionalized compounds.
From the preliminary studies, we suspect that an enantiose-
lective variant can be achieved and that this method can be
applied to the synthesis of other fused ring systems. Future
investigations within the group will continue to explore the
scope of novel modes of reactivity furnished by phosphines
and other nucleophilic catalysts.
[9] B. M. Trost, U. Kazmaier, J. Am. Chem. Soc. 1992, 114, 7933 –
7935. The dienone, when formed, is not converted into the
diquinane under our conditions.
[10] S. Matsuzawa, Y. Horiguchi, E. Nakamura, I. Kuwajima,
Tetrahedron 1989, 45, 349 – 362.
Experimental Section
[11] Phosphepine 3 was originally developed as a chiral ligand for
transition-metal-catalyzed reactions. For the initial report, see:
Y. Chi, X. Zhang, Tetrahedron Lett. 2002, 43, 4849 – 4852.
[12] More recently, phosphepine 3 has been employed as a chiral
nucleophilic catalyst. For early reports, see references [3a] and
[3b].
[13] The absolute stereochemistry of the product has not yet been
determined.
[14] For some examples of natural products that include a cis-
hydrindane subunit, see: B. M. Trost, C. D. Haffner, D. J.
Jebaratnam, M. J. Krische, A. P. Thomas, J. Am. Chem. Soc.
1999, 121, 6183 – 6192.
General procedure: A flask charged with the substrate was evacuated
and refilled with argon three times. The appropriate volume of
CH2Cl2:EtOAc (9:1) was added to afford a 0.01m solution of the
substrate. PnBu3 (0.20 equiv) was added by syringe, and the solution
was stirred for 20 h at room temperature. The reaction mixture was
then exposed to air for 1 h, filtered through a short pad of silica gel
with Et2O washings (100 mL), and concentrated. The desired product
was obtained by flash chromatography.
Received: September 12, 2009
Published online: November 26, 2009
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