Cu(I)-catalyzed hetero-Diels-Alder reaction between danishefsky-type siloxy dienes and ketones

Article abstract of DOI:10.1021/ol802134a

(Chemical Equation Presented) A general catalytic method for the hetero-Diels - Alder reaction between Danishefsky-type siloxy dienes and ketones was developed. Optimum results were produced with a catalyst generated from CuOTf·(C₆H₆)_1/2 and TBAT with Ph ₃PO as the catalytic additive. This reaction was extended to an asymmetric variant, using a Cu(I)-Walphos catalyst.

Full text of DOI:10.1021/ol802134a

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5151-5154
Cu(I)-Catalyzed Hetero-Diels-Alder
Reaction between Danishefsky-Type
Siloxy Dienes and Ketones
I-Hon Chen, Kounosuke Oisaki, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received September 12, 2008
ABSTRACT
A general catalytic method for the hetero-Diels-Alder reaction between Danishefsky-type siloxy dienes and ketones was developed. Optimum
results were produced with a catalyst generated from CuOTf·(C6H6)1/2 and TBAT with Ph3PO as the catalytic additive. This reaction was extended
to an asymmetric variant, using a Cu(I)-Walphos catalyst.
Catalytic asymmetric construction of molecules containing
tetrasubstituted carbons is a critical challenge in organic
synthesis.1 Such molecules can be unique and useful
pharmaceutical leads in medicinal chemistry.2 Dihydropy-
ranones are versatile components of various biologically
active compounds.3 One of the most direct methods for the
synthesis of dihydropyranones is the hetero-Diels-Alder
reaction between the Danishefsky’s diene or its derivatives
and carbonyl-containing compounds.4 Catalytic asymmetric
hetero-Diels-Alder reactions to produce enantiomerically
enriched dihydropyranones are currently limited, however,
to the use of aldehydes5 and R-ketoesters6 as dienophiles.7
The corresponding reaction of simple ketones has yet to be
developed because the reactivity of ketones is attenuated
compared with that of aldehydes and R-ketoesters. Herein,
we report the first entry in this category using Cu(I) catalysis.
Although there are some reports of racemic hetero-
Diels-Alder reactions of ketones,8 their substrate generality
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Fuji, K. Chem. ReV. 1993, 93, 2037. (c) Christoffers, J.; Mann,
A. Angew. Chem., Int. Ed. 2001, 40, 4591. (d) Denissova, I. Tetrahedron
2003, 59, 10105. (e) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004,
43, 284. (f) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108, 2853. (g)
Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873. (h) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969. (i)
Hatano, M.; Ishihara, K. Synthesis 2008, 1647.
(4) For reviews of hetero-Diels-Alder reactions, see: (a) Kobayashi,
S.; Jørgensen, K. A. Cycloaddition Reactions in Organic Synthesis; Wiley-
VCH: Weinheim, Germany, 2002. (b) Jørgensen, K. A. Angew. Chem., Int.
Ed. 2000, 39, 3558. (c) Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093.
(d) Gouverneur, V.; Reiter, M. Chem. Eur. J. 2005, 11, 5806. (e) Lin, L.;
Liu, X.; Feng, X. Synlett 2007, 2147.
(2) For examples, see: (a) Pommier, Y.; Kohlhagen, G.; Kohn, K. W.;
Leteurtre, F.; Wani, M. C.; Wall, M. E. Proc. Natl. Acad. Sci. U.S.A. 1995,
92, 8861 (camptothecins). (b) Como, J. A.; Dismukes, W. J. New Engl.
J. Med. 1994, 330, 263 (triazole antifungals).
(3) For example, see: Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.;
Borchardt, A.; Dragovich, P.; Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.;
Parge, H.; Love, R.; Hickey, M.; Doan, C.; Shi, S.; Duggal, R.; Lewisc,
C.; Fuhrman, S. Bioorg. Med. Chem. Lett. 2006, 16, 4834 (HCV RNA
polymerase inhibitors).
(5) For examples, see: (a) Doyle, M. P.; Phillips, I. M.; Hu, W. J. Am.
Chem. Soc. 2001, 123, 5366, and references cited therein. (b) Yang, X.-B.;
Feng, J.; Zhang, J.; Wang, N.; Wang, L.; Liu, J.-L.; Yu, X.-Q. Org. Lett.
2008, 10, 1299. (c) Du, H.; Zhang, X.; Wang, Z.; Bao, H.; You, T.; Ding,
K. Eur. J. Org. Chem. 2008, 2248, and references cited therein.
10.1021/ol802134a CCC: $40.75
Published on Web 10/30/2008
2008 American Chemical Society

is not satisfactory. Prior to this report, the most successful
example of this has been Rawal’s reaction using 1-amino-
3-siloxybutadiene (Rawal’s diene) through hydrogen-bonding
activation of ketones with protic solvents.8a Although the
use of reactive cyclic ketones in these reactions produces
high yields (up to 85%), aliphatic ketones produce only
moderate yields (33-44%), and the use of aromatic ketones
has not been described. Therefore, the development of
catalytic hetero-Diels-Alder reaction of ketones with a
synthetically useful substrate scope is very challenging.
hypothesized that the Danishefsky’s diene (1a) would be
activated by a CuF catalyst [existing as copper silicate 4 in
the presence of (EtO)3SiF] through transmetalation, similar
to ketene silyl acetals, generating the corresponding copper
enolate 5 (Scheme 1). The copper enolate should be reactive
enough, and the addition to ketones 2 would be possible.
The resulting copper aldolate 6 would be expected to cyclize
via a sequential conjugate addition followed by the elimina-
tion of copper methoxide. Finally, catalytically active copper
silicate 4 would be regenerated by trapping copper methoxide
with (EtO)3SiF.
On the basis of this hypothesis, we first applied the
optimized conditions of the aldol reaction to ketones
[CuF·3PPh3·2EtOH complex as a catalyst (10 mol %) in
the presence of (EtO)3SiF (120 mol %)] to the hetero-
Diels-Alder reaction between acetophenone (2a) and
siloxy diene 1a at room temperature.12 The desired
cyclized product 3a was obtained in 24% yield (Table 1,
Scheme 1
.
Hypothesized Catalytic Cycle of Copper(I)-Catalyzed
Hetero-Diels-Alder Reaction
Table 1. Optimization of Reaction Conditions
Ph3PO
(mol %)
yield
(%)a
entry
catalyst
CuF·3PPh3·2EtOH
1
2
3
4
5
6
7e
0
0
0
0
0
24
43
0
CuF·3PPh3·2EtOH + tol-BINAPb
CuOTfc + CsF + rac-BINAPd
CuOTfc + NaF + rac-BINAPd
CuOTfc + TBAT + rac-BINAPd
CuOTfc + TBAT + rac-BINAPd
CuOTfc + TBAT + rac-BINAPd
Our initial plan to realize the catalytic hetero-Diels-Alder
reaction between the Danishefsky’s diene (1a)9 and ketones
was based on the previous development of a CuF-catalyzed
aldol reaction to ketones.10 In this aldol reaction, various
ketones and ketene silyl acetals were reacted in the presence
of a CuF·3PPh3·2EtOH catalyst (2.5 mol %) and a stoichio-
metric amount of (EtO)3SiF. High reactivity was attributed
to the generation of highly nucleophilic copper enolates
through transmetalation of the silyl enolates.11 (EtO)3SiF
efficiently trapped the intermediate copper aldolate, facilitat-
ing the turnover-limiting catalyst regeneration step. We
0
70
77
8
10
10
a Isolated yield. b 20 mol % of tol-BINAP was added. c CuOTf·(C6H6)1/2
.
d 12 mol % of racemic BINAP was added. e In the absence of (EtO)3SiF.
entry 1). The addition of tol-BINAP (20 mol %) slightly
improved the yield (43%: entry 2). To further improve
these promising results, we screened catalytic combina-
tions of a CuOTf·(C6H6)1/2-racemic BINAP complex and
several fluoride sources, expecting that the CuF-BINAP
complex would be generated in situ. The reaction did not
proceed with the use of CsF or NaF as the fluoride source
(entries 3 and 4), but the yield of 3a markedly improved
to 70% with the use of TBAT (tetrabutylammonium
difluorotriphenylsilicate)13 (entry 5).14 Copper triflate
(6) (a) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jørgensen,
K. A. J. Am. Chem. Soc. 1998, 120, 8599. (b) Ghosh, A. K.; Shirai, M.
Tetrahedron Lett. 2001, 42, 6231. (c) Dalko, P. I.; Moisan, L.; Cossy, J.
Angew. Chem., Int. Ed. 2002, 41, 625. (d) Furuno, H.; Kambara, T.; Tanaka,
Y.; Hanamoto, T.; Kagawa, T.; Inanaga, J. Tetrahedron Lett. 2003, 44, 6129.
(e) Zhuang, W.; Poulsen, T. B.; Jørgensen, K. A. Org. Biomol. Chem. 2005,
3, 3284. (f) Akullian, L. C.; Snapper, M. C.; Hoveyda, A. H. J. Am. Chem.
Soc. 2006, 128, 6532. (g) Landa, A.; Richter, B.; Johansen, R. L.; Minkkila¨,
A.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 240.
(7) For a racemic example using ketones, see: Liu, J.; Li, X.; Wang, J.;
Feng, X. AdV. Synth. Catal. 2006, 348, 939.
(8) (a) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662.
(b) Kitazawa, T.; Mukaiyama, T. Heterocycles 2006, 69, 417. (c) Guay,
V.; Brassard, P. Tetrahedron 1984, 40, 5039.
(12) No reaction proceeded with Cu(OTf)2 or CuF2 catalyst.
(13) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc.
1995, 117, 5166.
(9) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J. J. Am. Chem.
Soc. 1979, 101, 6996.
(14) The results of Table 1, entries 2-5, suggest that the tetrabutylam-
monium cation facilitates the catalytic cycle. The fact that 3a was obtained
in 90% yield with CuF·3PPh3·2EtOH-tol-BINAP catalyst (10 mol %) in
the presence of 30 mol % of Bu4N·BF4 (cf. 43% yield in the absence of
Bu4N·BF4, Table 1, entry 2) supports this consideration. We assume that
the tetrabutylammonium cation facilitates the catalyst regeneration step from
intermediate 6 via ion exchange. See the Supporting Information for detailed
discussion.
(10) (a) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 5644. (b) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2006, 128, 7164.
(11) For pioneering studies on transmetalation from a silyl enolate to a
copper enolate, see: Pagenkopf, B. L.; Kru¨ger, J.; Stojanovic, A.; Carreira,
E. M. Angew. Chem., Int. Ed. 1998, 37, 3124.
5152
Org. Lett., Vol. 10, No. 22, 2008

could not be replaced by copper(I) chloride, copper(I)
iodide, or copper(I) acetate. Racemic BINAP was the most
suitable ligand, and other phosphines such as dppe, dppf,
and xantphos produced much less satisfactory results (less
than 5% yield). Finally, the yield and reaction rate were
improved further in the presence of a Lewis basic
Consistent with the observation in the previous aldol
reaction to ketones,10 there was no catalyst turnover in
the absence of (EtO)3SiF (entry 7).
Under the optimized conditions, we investigated the
substrate scope of the catalytic hetero-Diels-Alder reaction
(Table 2). Various aromatic ketones generally produced high
chemical yields (entries 1-10). Specifically, styrene ketone
2d, which polymerized under acidic conditions, was tolerated
(entry 4). Unique spiro-products 3i, 3j, and 3k were obtained
in high yields with the use of unsymmetrical cyclic ketones
(entries 9-11). In the reaction of cyclohexenone 2k, hetero-
Diels-Alder product 3k was produced exclusively and no
detectable amounts of the Diels-Alder product were gener-
ated (entry 11). Aliphatic ketones were also competent
substrates, affording the products in synthetically useful
yields (entries 12 and 13).
Table 2. Substrate Scope of Cu(I)-Catalyzed
Hetero-Diels-Alder Reaction of Ketones
At this stage, a general catalytic hetero-Diels-Alder
reaction of ketones was developed, but the consumption of
a stoichiometric amount of silyl fluoride was unsatisfactory
with regard to atom economy.16 On the basis of the
hypothetical catalytic cycle shown in Scheme 1, we expected
that if the triethoxysilyl version of the Danishefsky’s diene
(1b) was used, (EtO)3SiF would be generated at the initial
transmetalation step, instead of TMSF (from 4 to 5 in Scheme
1). The generated (EtO)3SiF should then act as a CuOMe
trapping reagent in the catalyst regeneration step. A more
atom-economical catalytic system could thus be constructed
without forming a stoichiometric amount of waste TMSF.
Triethoxysiloxy diene 1b was prepared on a gram scale by
using the same procedure as that for Danishefsky’s diene
1a9 (Scheme 2, eq 1).
Scheme 2. Synthesis of Triethoxysiloxy Diene 1b (Eq 1) and
Simplified Catalytic Hetero-Diels-Alder Reaction of Ketones
Using 1b (Eq 2)
a Isolated yield.
triphenylphosphine oxide as an additive (entry 6).15
Notably, on the basis of NMR and TLC analysis, aldol
intermediate (silylated 6) was not detected in the reaction
mixture, and cyclized 3a was the major product even
before adding aqueous HCl to quench the reaction.
Representative results using the new diene 1b in the
absence of the (EtO)3SiF additive are summarized in Scheme
2, eq 2. Comparable results were obtained with ketones 2c
and 2h under the conditions described in Table 2. Therefore,
a stoichiometric amount of (EtO)3SiF was not required to
(15) Triphenylphosphine oxide would coordinate to the silicon atom and
generate a pentacoordinated silicon. This species is more Lewis acidic than
the original tetracoordinated silicon (for a leading reference, see: Denmark,
S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D J. Am. Chem. Soc. 2005,
127, 3774. ), and should readily accept the counterion (fluoride or alkoxide)
of copper. Because copper silicate formation is the initiating step of
transmetalation between silicon and copper, formation of a pentacoordinated
silicon would facilitate the active copper enolate formation from 1a and
1b. See the Supporting Information for details.
(16) Trost, B. M. Science 1991, 254, 1471.
Org. Lett., Vol. 10, No. 22, 2008
5153

maintain reactivity under these simplified and more atom-
economical conditions.
and enantioselectivity were not quite satisfactory, to our
knowledge, this is the first example of a catalytic
enantioselective hetero-Diels-Alder reaction of ketones
reported to date. The synthesis of 3 in an enantiomerically
enriched form using alternative synthetic methodologies
is not simple. The absolute configuration of the products
was determined to be (R) by conversion to a known
compound17 and by X-ray crystallography (Figure 1).19
This method was next extended to the catalytic enan-
tioselective hetero-Diels-Alder reaction of ketones. Screen-
ing of chiral phosphines17 led us to identify Walphos-
type diphosphines as the optimized chiral ligand (Table
3).18 The use of ethyl acetate as the solvent afforded better
Table 3. Substrate Scope of Cu(I)-Catalyzed Asymmetric
Hetero-Diels-Alder Reaction of Ketones
Figure 1. X-ray crystallography of compound 3b.
In summary, we developed a general catalytic method for
a hetero-Diels-Alder reaction between Danishefsky-type
siloxy dienes and ketones. A Cu(I) catalyst generated from
CuOTf and TBAT produced the highest activity. Due to the
development of new triethoxysiloxy diene 1b, only a catalytic
amount of the fluoride source was required. This method
was extended to the first catalytic asymmetric hetero-
Diels-Alder reaction of ketones using chiral Cu(I)-Walphos
complexes. Futher studies to improve the enantioselectivity
and substrate generality, as well as detailed mechanistic
studies, are ongoing.
a Isolated yield. b Determined by chiral HPLC analysis. c The absolute
configuration of the products was determined to be (R).
enantioselectivity than THF. High to moderate enantiose-
lectivity was obtained from aromatic ketones. Unfortu-
nately, aliphatic ketones produced unsatisfactory results
(no reaction or less than 10% ee) under the catalytic
asymmetric conditions. Although the substrate generality
Acknowledgment. Financial support was provided by
Grant-in-Aid for Scientific Research (S) and (B) from JSPS,
and that for Priority Areas “Chemistry of Concerto Catalysis”
from MEXT.
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) See the Supporting Information for details.
(18) Using 1a and a stoichiometric amount of (EtO)3SiF produced
comparable yields and enantioselectivities to the simplified method with
1b shown in Table 3. The observed comparable enantioselectivities between
the two methods strongly support that the actual active species is the identical
copper enolate, which is generated through transmetalation of the siloxy
dienes.
OL802134A
(19) Interestingly, the aryl group, which is bulkier than the methyl group,
exists at the axial position in this crystal structure.
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Org. Lett., Vol. 10, No. 22, 2008