Diastereoselective oxidative carbon-carbon bond formation via silyl bis-enol ethers

Article abstract of DOI:10.1021/ol802516z

(Chemical Equation Presented) Diisopropylsilyl bis-enol ethers are shown to be powerful intermediates for the diastereoselective dimerization and cross-coupling of cyclic ketones. The trends observed for the oxidative coupling of a range of different dial

Full text of DOI:10.1021/ol802516z

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5621-5624
Diastereoselective Oxidative
Carbon-Carbon Bond Formation via
Silyl Bis-enol Ethers
Christopher T. Avetta, Jr., Leah C. Konkol, Carla N. Taylor, Karen C. Dugan,
Charlotte L. Stern, and Regan J. Thomson*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
r-thomson@northwestern.edu
Received October 30, 2008
ABSTRACT
Diisopropylsilyl bis-enol ethers are shown to be powerful intermediates for the diastereoselective dimerization and cross-coupling of cyclic
ketones. The trends observed for the oxidative coupling of a range of different dialkylsilyl bis-enol ethers derived from cyclohexanone are
rationalized by invoking a stereochemical model based on a Thorpe-Ingold effect.
Reliable bond-forming reactions that produce multiple ste-
reocenters are of significant strategic value for the synthesis
of complex natural products since retrosynthetic application
of such transformations allows for rapid clearance of
stereocenters while simultaneously enforcing a convergent
synthesis plan.1 As part of our program directed toward
synthesizing bioactive polycyclic molecules, we sought to
develop methods to effect the stereocontrolled oxidative
coupling of cyclic ketones and thus provide a convergent
route to linked bicyclic ring systems prevalent in numerous
natural products, such as the lomaiviticins.2 The oxidative
coupling of enolates has been known for over 70 years,3 but
it is only in relatively recent times that synthetically useful
procedures for cross-coupling have emerged.4 Recently, we
demonstrated the utility of silyl bis-enol ethers for controlled
cross-coupling and quaternary stereocenter generation.5
Despite these advances, it is still difficult to conduct the
cross-coupling of substrates with similar oxidation potentials,
and diastereoselective cross-coupling remains largely unde-
veloped.
Previous literature reports have shown that the dimerization
of lithium enolates or trimethylsilyl enol ethers derived from
cyclohexanone produce the 1,4-diketone in modest yield and
with low levels of diastereocontrol.6 Schmittel and co-
workers have shown that silicon-tethered enol silanes may
be used to prepare the dimer of propiophenone with good
(1) Corey, E. J.; Cheng, X-M. The Logic of Chemical Synthesis; John
Wiley & Sons: New York, 1989.
(2) He, H. Y.; Ding, W. D.; Bernan, V. S.; Richardson, A. D.; Ireland,
C. M.; Greenstein, M.; Ellestad, G. A.; Carter, G. T. J. Am. Chem. Soc.
2001, 123, 5362–5363.
(3) Ivanoff, D.; Spassoff, A. Bull. Soc. Chim. Fr. 1935, 2, 76–78.
(4) (a) Baciocchi, E.; Casu, A.; Ruzziconi, R. Tetrahedron Lett. 1989,
30, 3707–3710. (b) Fujii, T.; Hirao, T.; Ohshiro, Y. Tetrahedron Lett. 1992,
33, 5823–5826. (c) Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M.
Chem. Lett. 1992, 2099–2102. (d) Baran, P. S.; DeMartino, M. P. Angew.
Chem., Int. Ed. 2006, 45, 7083–7086. (e) Jang, H. Y.; Hong, J. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004–7005. (f) Beeson,
T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.; MacMillan, D. W. C.
Science 2007, 316, 582–585. (g) DeMartino, M. P.; Chen, K.; Baran, P. S.
J. Am. Chem. Soc. 2008, 130, 11546–11560.
(5) Clift, M. D.; Taylor, C. N.; Thomson, R. J. Org. Lett. 2007, 9, 4667–
4669.
(6) (a) Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97,
649–651. (b) Kobayashi, Y.; Taguchi, T.; Tokuno, E. Tetrahedron Lett.
1977, 3741–3742. (c) Fujii, T.; Hirao, T.; Ohshiro, Y. Tetrahedron Lett.
1992, 33, 5823–5826. (d) Hoffmann, H. M. R.; Mu¨nnich, I.; Nowitzki, O.;
Stucke, H.; Williams, D. J. Tetrahedron 1996, 52, 11783–11798.
(7) (a) Schmittel, M.; Burghart, A.; Malisch, W.; Reising, J.; Sollner,
R. J. Org. Chem. 1998, 63, 396–400. (b) Schmittel, M.; Haeuseler, A. J.
Organomet. Chem. 2002, 661, 169–179.
10.1021/ol802516z CCC: $40.75
Published on Web 11/18/2008
2008 American Chemical Society

stereoselectivity,7a,8 and they have reported a single example
of a diastereoselective cross-coupling between propiophenone
and 1-p-tolylpropan-1-one.7b Given the synthetic potential
of these silyl bis-enol ethers, it is somewhat surprising that
these are the only diastereoselective examples reported in
the literature. Our interest in preparing complex linked
bicyclic structures led us to explore the generality of silyl
bis-enol ethers for preparing synthetically useful intermedi-
ates beyond the acyclic aryl ketones explored by Schmittel
and co-workers. We now report general conditions to enable
oxidative dimerization and cross-coupling of cyclic ketones
in good yield and with high diastereoselectivities.
Table 2. Diastereoselective Dimerization of i-Pr2Si-enol Ethers
Table 1. Influence of Silicon Substituents on Stereoselectivity
a Diastereomeric ratio determined by 1H NMR spectroscopy on
unpurified reaction mixture. b Isolated yield of 2 after chromatography.
We initiated our research by preparing the dimethylsilyl
bis-enol ether derived from cyclohexanone (i.e., 1a)9 and
conducted the oxidative coupling using a mixture of ceri-
um(IV) ammonium nitrate (CAN) and NaHCO3. Under these
conditions, we obtained a low yield and modest stereose-
lectivity for the chiral isomer 2 over the meso-isomer 3
(Table 1, entry 1). While we were encouraged by the modest
stereoselectivity, we were disappointed with the low yield
obtained. Consequently, we elected to investigate a number
of variables that might influence both the yield and stereo-
selectivity of this bond-forming process. We found that the
size of the silicon substituents had a dramatic effect on both
of these variables. While diethylsilyl ether 1b afforded dione
2 as a 5:1 mixture of diastereomers and with an improved
yield (Table 1, entry 2), the bulkier diisopropylsilyl ether
1c gave 2 as a 10:1 mixture in 57% yield (Table 1, entry 3).
The diphenyl and cyclic silyl ethers (Table 1, entries 4-6)
a Isolated yield. b Determined by 1H NMR spectroscopy on the unpurified
reaction mixture.
all provided lower levels of stereocontrol than diisopropyl-
silane 1c, so this system was selected for further develop-
ment.10
During the course of optimizing the formation of dione 2
from 1c, we found that a 6:1 mixture of acetonitrile to
propionitrile in the presence of DMSO (2.0 equiv) enhanced
substrate solubility and provided improved stereoselectivity
(67% yield, 14:1 dr) (Table 2). The results for a number of
ketone dimerizations via diisopropylsilyl bis-enol ethers are
displayed below; in all cases investigated, the major dias-
tereomer was that shown.11
Unsaturation was tolerated on the substrates, although the
absence of significant steric hindrance resulted in lower levels
of stereoinduction (i.e., 4 and 5). Tetralone dimer 6 was
(8) A number of diastereoselective dimerizations of chiral carboxylate
derivatives have been reported. For a review summarizing this area of
research, see: Csa´ky¨, A. G.; Plumet, J. Chem. Soc. ReV. 2001, 30, 313–
(10) We were unable to prepare the di-t-Bu bis-enol ether.
(11) See the Supporting Information for details related to stereochemical
proofs.
(12) Mazzega, M.; Fabris, F.; Cossu, S.; De Lucchi, O.; Lucchini, V.;
Valle, G. Tetrahedron 1999, 55, 4427–4440.
320
.
(9) Prepared according to: Rathke, M. W.; Weipert, P. D. Synth.
Commun. 1991, 21, 1337–1351. See the Supporting Information for further
details of bis-enol ether synthesis.
5622
Org. Lett., Vol. 10, No. 24, 2008

formed in good yield and with high levels of stereocontrol
(77% yield, 20:1 dr). Geminal substitution was tolerated;
diones 7 and 8 were produced with 10:1 selectivity. The
dimerization of (R)-carvone to afford dimer 912 proceeded
in good yield and with 20:1 diastereoselection. The high
selectivity of this reaction establishes that both the ring
substituents and the effect of the silicon tether are mutually
reinforcing. Lastly, cyclopentanone gave dione 106d in 57%
yield and with moderate selectivity (7:1), while cyclohep-
tanone provided the corresponding dimer 116d in 50% yield
as a 14:1 mixture of diastereomers.
however. To extend this diastereoselective process and thus
enable such cross-coupling, we prepared a number of
unsymmetrical silyl bis-enol ethers.14 Exposure of the
unsymmetrical substrates to our previously developed condi-
tions afforded the cross-coupled products with variable yields
and selectivities (Table 3).11 For a number of substrates, the
yields and diastereoselectivities were high. The cross-coupled
products derived from carvone (i.e., 16, 17, 18, and rac-19)
demonstrate the potential power of this chemistry to generate
contiguous stereoarrays. Interestingly, the coupling of the
meso-silyl bis-enol ether derived from (R)- and (S)-carvone
furnished the racemic product 19 in preference to the two
possible meso-isomers (61% yield, 5:1 ratio of rac-19 to
other isomers).
Table 3. Stereoselective Cross-Coupling of i-Pr2Si-enol Ethers
Figure 1. Model for stereoselectivity.
We have rationalized the inherent selectivity for the
observed stereochemistry by considering the two possible
conformations of the intermediate radical-cations that would
lead to the diastereomeric products (I and II in Figure 1).15
b
a Isolated yield. Determined by H NMR spectroscopy on unpurified
reaction mixture. c Stereochemistry assigned by analogy. d Refers to the
ratio of the major isomer to the mixture of minor isomers.
1
The establishment of stereocontrolled oxidative dimeriza-
tion of ketones is an important goal since it may enable
access to bioactive dimeric natural products.13 Diastereose-
lective oxidative cross-coupling is a more challenging goal,
Figure 2. Models for the impact of resident stereocenters.
Reactions proceeding through conformation I avoid de-
stabilizing interactions between the two rings that are present
in conformation II. The enhanced selectivity observed with
larger silicon substituents may be due to a Thorpe-Ingold
effect (see III).16 Here, the larger diisopropyl groups cause
an increase in the angle θ and a corresponding compression
(13) Shair and co-workers reported a stereoselective oxidative enolate
dimerization en route to the core of lomaiviticin A; see: Krygowski, E. S.;
Murphy-Benenato, K.; Shair, M. D. Angew. Chem., Int. Ed. 2008, 47, 1680–
1684.
(14) See the Supporting Information for procedures regarding substrate
synthesis.
(15) Schmittel and co-workers postulated similar conformations for the
substrates they investigated; see ref 7.
Org. Lett., Vol. 10, No. 24, 2008
5623

of angle γ, which ultimately increases the destabilization of
II. These bond angle differences are seen in the X-ray crystal
structures of Et2Si(OH)2 (O-Si-O ) 109.8°)17a and
i-Pr2Si(OH)2 (O-Si-O ) 106.6°).17b We speculate that the
effect of the DMSO additive might be due to the interme-
diacy of hypervalent silicon species18 and are actively
investigating this possibility.
substituents are subordinate to the conformational bias
imparted by the silicon tether.
The diastereomeric ratios we observed for these cross-
coupling reactions (up to 20:1 dr) are, to the best of our
knowledge, the highest reported to date. As a point of
comparison, the conditions developed by Baran and co-
workers4d,g for enolate cross-coupling afforded a maximum
diastereomeric ratio of 2.8:1.
The substrates derived from carvone enable the impact of
resident stereocenters on the stereochemical outcome to be
determined. Three situations were investigated (Figure 2):
the cross-coupling of (R)-carvone with achiral ketones (via
bis-enol IV), the dimerization of (R)-carvone (via bis-enol
V), and the coupling of (R)- and (S)-carvone (via VI). In all
instances, the stereochemistry of the newly formed centers
reflects that the reaction most likely proceeded through a
conformation akin to I in Figure 1. For the reaction of bis-
enol IV, the isopropenyl group effectively blocks one face
of the substrate so that the newly formed bond is generated
opposite the ꢀ-substituent (15:1 dr with cyclohexanone). For
the (R,R)-carvone dimer 9, bond formation most likely occurs
through conformer V, where both substituents are positioned
away from the forming bond. In the (R,S)-carvone system
(i.e., rac-19), bond formation proceeds through conformer
VI, but syn to one isopropenyl group and anti to the other.19
From this last example, we conclude that the effects of ring
Future research in our group will further probe the impact
that resident stereocenters have on the stereochemical
outcome of these couplings, particularly when the two
substituents are different (i.e., not both isopropenyl groups).
Application of silyl bis-enol ethers to the construction of
complex polycyclic molecules should enable convergent and
concise syntheses, while investigations into Lewis base
effects during oxidative coupling might open avenues for
asymmetric induction.
Acknowledgment. This work was supported by North-
western University (NU) and the NU Intergrated Molecular
Structure and Education Research Center (NSF Grant Nos.
DMR0114235 and CHE9871268). K.D. acknowledges the
award of a Northwestern Undergraduate Research Grant. We
thank Prof. K. A. Scheidt (NU) and Mr. M. D. Clift (NU)
for helpful discussions.
(16) For a review, see: Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105,
1735–176.
Supporting Information Available: Experimental pro-
cedures, spectral data, stereochemical proofs, and models.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Tomlins, P. E.; Lydon, J. E.; Akrigg, D.; Sheldrick, B. Acta
Crystallogr. C 1985, 41, 941–942. (b) Buttrus, N. H.; Eaborn, C.; Hitchcock,
P. B.; Lickiss, P. D. J. Organomet. Chem. 1986, 302, 159–163.
(18) For a recent review of synthetic processes involving hypervalent
silicon species, see: Rendler, S.; Oestreich, M. Synthesis 2005, 1727–1747.
(19) See the Supporting Information for a more detailed discussion.
OL802516Z
5624
Org. Lett., Vol. 10, No. 24, 2008