Catalytic enantioselective aldol reaction to ketones

Article abstract of DOI:10.1021/ja061815w

An enantioselective aldol reaction between ketones and ketene silyl acetals is described using CuF-chiral phosphine as a catalyst. The key for high enantioselectivity was the development of a novel ligand derived from Taniaphos combined with the unique ac

Full text of DOI:10.1021/ja061815w

Published on Web 05/09/2006
Catalytic Enantioselective Aldol Reaction to Ketones
Kounosuke Oisaki, Dongbo Zhao, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan
Received March 16, 2006; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Chiral tertiary alcohols are important building blocks and
Table 1. Ligand Screening and Optimization
ubiquitous subunits present in many biologically active compounds
and medicinal leads. They are difficult to produce, however, using
1
current synthetic methods. Catalytic enantioselective carbon-
nucleophile addition to simple ketones1d is a fundamental methodol-
ogy, constructing the new tetrasubstituted stereogenic carbon center
concomitant with carbon-carbon bond formation. Catalytic enan-
tioselective aldol reactions to simple ketones are among the most
synthetically useful reactions in this category. The following
inherent features of this type of reaction make its development
extremely challenging, compared to the catalytic enantioselective
aldol reaction to aldehydes:2 (1) attenuated reactivity of ketones
usually leads to low conversion; (2) retro-reaction is generally rapid;
and (3) enantioface discrimination is difficult due to the similar
electronic/steric nature between the two substituents of the ketone
carbonyl carbon. Therefore, catalysts that promote enantioselective
aldol reaction to ketones need to be highly active and discriminate
subtle differences between the two substituents on a prochiral
carbon.
,3
Because of these difficulties, there are currently only a few
4
reports of catalytic enantioselective aldol reaction to ketones,
including two from our group.5,6 All of these reactions have a
narrow substrate scope, however, especially on the nucleophile side,
which hampers practical utilization of these reactions. In this
Communication, we report a general enantioselective catalytic aldol
reaction to ketones.
a
Reaction was conducted with 4 mol % of L4 under 4 M DME at 0 °C.
Scheme 1. Plausible Catalytic Cycle and Effect of PhBF3K
We previously reported a general and mild aldol reaction between
ketones and ketene trimethylsilyl acetals catalyzed by a copper(I)
fluoride-phosphine complex.5 Mechanistic studies indicated that
a copper enolate generated through transmetalation is the actual
nucleophile, and the addition of a stoichiometric amount of
a
3
(EtO) SiF to facilitate the rate-determining catalyst turnover is
essential. More recently, we demonstrated promising results toward
enantioselective extension.5b A deep chiral environment around Cu
constructed by a chiral diphosphine ligand was determined to be
necessary to efficiently shield one enantioface of the ketone.
On the basis of this knowledge, we rescreened diphosphine
7
ligands. Taniaphos L1 was found to be a promising lead for our
aldol reaction between ketone 1a and ketene silyl acetal 2a (Table
1, entry 1). To maximize efficiency, we tuned the ligand structure.
We mainly focused on tuning the amine moiety because molecular
modeling studies indicated that bulky amine substituents could fix
the position of the cyclohexyl groups, which is an essential
requirement for effective enantioselection. Indeed, enlargement of
the amine moiety improved the enantioselectivity; however, the
reactivity decreased dramatically (entry 2). In addition, the silyl
enol ether derived from 1a was produced (ca. 10%) as a side
product. The undesired side reaction is likely promoted by an
intermediate copper aldolate (see C in Scheme 1) working as a
strong Br o¨ nsted base. To improve the yield, various additives were
3
3). Increasing the amount of (EtO) SiF and decreasing the amount
of 2a further improved the yield (entry 4). The ligand was further
tuned using these conditions (entries 5-10). Finally, we identified
di-n-butylamine-type Taniaphos L4 as the optimum ligand. Using
screened. The addition of 10 mol % of PhBF
3
K significantly
improved the yield without affecting the enantioselectivity (entry
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9
J. AM. CHEM. SOC. 2006, 128, 7164-7165
10.1021/ja061815w CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Aldol Reaction to Ketonesa
addition of a catalytic amount of PhBF
3
K simply increases the
concentration of D, intensifying its acceleration effect. In fact, using
10
(
MeO)
2
SiF
2
3 3
instead of (EtO) SiF (in the absence of PhBF K)
under the conditions listed in Table 1, entry 2 significantly improved
the yield of 3aa (22 h, 97% yield, 60% ee).
In conclusion, we developed a general enantioselective Cu(I)
fluoride-catalyzed aldol reaction to simple ketones, identifying
3
PhBF K as an effective catalytic additive. Remarkably, the robust-
ness of this reaction allowed for the first diastereo- and enantiose-
lective catalytic aldol reaction to ketones using ketene silyl acetals.
To achieve the excellent selectivity, steric tuning of the Taniaphos
ligand was essential. A unique role of PhBF K as a fluoride source
3
to generate the active trapping silyl agent D was demonstrated.
Further detailed mechanistic studies will be reported elsewhere.
Acknowledgment. Financial support was provided by a Grand-
in-Aid for Specially Promoted Research of MEXT. K.O. thanks
JSPS for research fellowships.
Supporting Information Available: Experimental procedures and
characterization of the products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(
1) (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (b)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (c) Corey,
E. J.; Gunzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (d) For
recent examples of catalytic enantioselective additions to simple ketones,
see ref 6c and references therein.
(2) Recent selected review: Palomo, C.; Oiarbide, M.; Garc ´ı a, J. M. Chem.
Soc. ReV. 2004, 33, 65.
(
3) For metal fluoride-catalyzed asymmetric aldol reaction to aldehydes,
see: (a) Kr u¨ ger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 867.
(b) Pagenkopf, B. L.; Kr u¨ ger, J.; Stojanovic, A.; Carreira, E. M. Angew.
Chem., Int. Ed. 1998, 37, 3124. (c) Yanagisawa, A.; Nakatsuka, Y.;
Asakawa, K.; Kageyama, H.; Yamamoto, H. Synlett 2001, 69. (d)
Yanagisawa, A.; Nakatsuka, Y.; Asakawa, K.; Wadamoto, M.; Kageyama,
H.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2001, 74, 1477. (e) Wadamoto,
M.; Ozasa, N.; Yanagisawa, A.; Yamamoto, H. J. Org. Chem. 2003, 68,
5593.
a
The detailed procedure is described in the Supporting Information. b
5
c
mol % of CuF and 8 mol % of L4 were used. 20 mol % of PhBF3K was
used. Absolute configuration was determined to be S. More polar isomer.
Less polar isomer. Absolute configuration was determined to be (2R,
S).
d
e
f
g
3
this ligand, both yield and enantioselectivity improved under higher
concentrations (4 M) at 0 °C (entry 11).
Next, we investigated the substrate generality under the optimized
conditions (Table 2). From various aromatic ketones (entries 1-4,
, 12), including a heteroaromatic ketone (entry 5), aldol products
were obtained in excellent yield with high enantioselectivity. This
method produces synthetically useful levels of enantioselection,
(4) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233. (b)
Denmark, S. E.; Fan, Y.; Eastgate, M. D. J. Org. Chem. 2005, 70, 5235.
(
2
c) Moreau, X.; Bazan-Tejeda, B.; Campagne, J.-M. J. Am. Chem. Soc.
005, 127, 7288.
6
(
5) (a) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
003, 125, 5644. (b) Oisaki, K.; Zhao, D.; Suto, Y.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2005, 46, 4325.
2
even with aliphatic ketones, substrates that have previously been
poor substrates for enantioselective aldol additions.4a,b Remarkably,
nucleophiles other than those that are acetate-derived can be used
(6) For catalytic enantioselective reductive aldol reaction to ketones, see: (a)
Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225. (b) Zhao, D.; Oisaki,
K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403. (c)
Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int.
Ed. 2006, 45, 1292.
(entries 9-11). The product diastereoselectivity was independent
of the E/Z ratio of silyl acetals (entries 9 and 10). These are the
first examples of catalytic enantio- and diastereoselective aldol
reactions of ketene silyl acetals to ketones.
(7) Taniaphos ligand L1 was purchased from Strem Chemicals, Inc. L2-L8
were prepared following the reported synthetic procedure. See Supporting
Information for details. (a) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse,
C.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 3212. (b) Ireland, T.;
Tappe, K.; Grossheimann, G.; Knochel, P. Chem. Eur. J. 2002, 8, 843.
NMR experiments were used to gain insight into the unique effect
of PhBF
in THF-d
3
K. When PhBF
3
K and (EtO)
3
SiF were mixed (3:5 ratio)
(8) The assignments are based on the chemical shift of synthesized (MeO)
MeO) SiF, PhBF , and commercial phenylpinacolborane. Alkoxyboron
acts as a much less effective trapping reagent according to the control
experiment using B(OMe) instead of the (EtO) SiF-PhBF K combina-
tion. See Supporting Information for details.
2 2
SiF ,
(
3
2
8
in an NMR tube, new peaks appeared: at -155 ppm in
19
19
2 2
F NMR, corresponding to (EtO) SiF ; at -158 ppm in F NMR,
3
3
3
1
1
corresponding to (EtO)SiF
corresponding to PhB(OEt)
3
; and at 12.2 ppm in B NMR,
. On the other hand, there was no
8
2
(9) Rate dependencies on [silyl acetal] and [CuF] (-0.8th and 1.5th,
respectively) suggested the intervention of the fluoride-rich silicon species
detectable interaction between PhBF
The NMR studies suggest that the beneficial effect of PhBF
is attributable to the generation of highly electrophilic (EtO) SiF
and (EtO)SiF (D in Scheme 1). In previous kinetic studies, these
species were thought to play a key role in the rate-determining
3
K, and CuF or 2a.
D in this rate-determining step, even in the absence of PhBF
3
K (ref 5a).
3
K
Other evidence that silyl fluoride is an important species in this reaction
t
is the finding that CuF-PPh
3
had higher catalyst activity than CuO Bu-
2
2
PPh or CuOAc-PPh
3
3
.
3
(
10) Tedious fractional distillation is required for the synthesis of (MeO)
2
SiF2.
5
a,9
catalyst turnover step, even in the absence of PhBF
3
K.
The
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