Catalytic enantioselective allylboration of ketones

Article abstract of DOI:10.1021/ja047200l

The first example of catalytic enantioselective allylboration and crotylboration of simple ketones is described. High enantioselectivity (up to 93% ee) was obtained using 3 mol % CuF-ⁱPr-DuPHOS as a chiral catalyst and 4.5 mol % La(Oⁱ

Full text of DOI:10.1021/ja047200l

Published on Web 07/01/2004
Catalytic Enantioselective Allylboration of Ketones
Reiko Wada,† Kounosuke Oisaki,† Motomu Kanai,*,†,‡ and Masakatsu Shibasaki*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan, and PRESTO,
Japan Science and Technology Corporation, Japan
Received May 13, 2004; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Lanthanide Effect on Catalytic Enantioselective
Allylboration of Ketones
The allylation reaction is one of the most useful carbon-carbon
bond-forming reactions in organic synthesis.1 There are highly
stereoselective (enantioselective and diastereoselective) catalytic
allylation and crotylation reactions2 using aldehydes as a substrate
to produce chiral secondary homoallyl alcohols. There are far fewer
successful examples, however, of targeting ketones as a substrate.3
Although high enantioselectivity is produced in some cases, only
toxic allylstannanes can be used as an allylating reagent, and these
reactions require high catalyst loading (10-30 mol %). In addition,
there are no reports of catalytic enantioselective crotylation of
ketones. Despite the importance of chiral tertiary homoallyl alcohols
as a chiral building block for biologically significant compounds,
there is little synthetic methodology available due to the attenuated
reactivity of ketones and the lesser steric dissimilarity of the two
substituents on the carbonyl carbon compared to aldehydes.4 We
report herein the first catalytic enantioselective allylboration of
ketones, which overcomes the above-mentioned hurdles in chiral
tertiary homoallyl alcohol synthesis.
We reported a general catalytic allylation using CuCl and TBAT
(tetrabutylammonium difluorotriphenylsilicate) as catalysts and
allyltrimethoxysilane as an allylation reagent.5 This reaction was
extended to a catalytic enantioselective allylation of ketones;
however, only moderate enantioselectivity (up to 61% ee using tol-
BINAP) was obtained using 15 mol % catalyst. To improve the
efficiency, we investigated use of allylboronates instead of allyl-
trimethoxysilane, on the basis of recent important findings that
allylboronates can be catalytically activated by a Lewis acid to
achieve stereoselective allylation of aldehydes.6
First, we found that catalytic allylation of various ketones,
including aromatic, heteroaromatic, R,â-unsaturated, and aliphatic
ketones, proceeded smoothly at ambient temperature in THF, using
1-3 mol % of catalyst (CuCl-TBAT or CuF‚3PPh3‚2EtOH7) and
commercially available pinacol 2-propenylboronic ester (2a: 1.1-3
equiv).8 Enones gave the 1,2-adducts with complete regioselectivity.
Therefore, allylboronates can be used with an efficiency comparable
to that of allyltrimethoxysilane in the CuF-catalyzed allylation to
ketones. The catalysis of CuF is due to an activation of the
allylboronate (see below), as was the case with allyltrimethoxy-
silane.5
catalyst
(x mol %)
2a
(y equiv)
time
(h)
yielda
(%)
eeb
(%)
entry
La-additive
1
2
3
4
5
15
15
3
15
15
3
3
1.2
3
3
-
20
3.5
1
42
95
94
52
48
79
77
82
80
79
La(OiPr)3
La(OiPr)3
(R)-BINOL-La(OiPr)3 20
(S)-BINOL-La(OiPr)3
20
a Isolated yield. b Determined by chiral HPLC.
and enantioselectivity through dual activation of the allylboronate
and the ketone by CuF and the additive Lewis acid, respectively.11
Specifically, we focused on the effect of lanthanides, taking
advantage of the dynamic coordinating nature of lanthanide metals.12
The addition of 20 mol % of La(OiPr)3 accelerated the reaction
between 1a and 2a in the presence of 15 mol % CuF-4 without
changing the enantioselectivity, and the product 3a was obtained
in 95% yield with 77% ee in 3.5 h (entry 2).13 The high reaction
rate allowed for a decrease in the catalyst loading; using 3 mol %
CuF-4 and 4.5 mol % La(OiPr)3, the reaction was completed in 1
h, giving 3a in 94% yield with improved 82% ee (entry 3). The
addition of La(OiPr)3 inhibited the CuF-catalyzed allylation using
allyltrimethoxysilane (yield < 5%), which clearly demonstrated the
advantage of the present allylboration reaction over the previous
allylsilylation.5
Substrate generality was investigated under the optimized condi-
tions (Table 2). High enantioselectivity (up to 91% ee) was obtained
from aromatic, heteroaromatic, cyclic, and aliphatic ketones, using
3 mol % catalyst in a short reaction time (1 h).14 Moreover, catalytic
enantioselective crotylation of ketones proceeded, and the product
was obtained with up to 93% ee (Table 3). No crotylation proceeded
in the absence of La(OiPr)3. Although the diastereoselectivity is
substrate-dependent and requires further improvement,8 this is the
first example of a catalytic enantioselective crotylation of ketones,
giving the chiral tetrasubstituted carbons with high enantioselec-
tivity.
We then extended this newly developed catalytic allylboration
of ketones to an enantioselective reaction. After intensive screening
of chiral ligands and optimization of the catalyst preparation
methods,9 the CuF catalyst prepared in situ from CuF2‚2H2O (15
The following preliminary investigations of the reaction mech-
anism provided pieces of meaningful information at the current
stage. First, we propose that the active nucleophile in the CuF-
catalyzed allylation reaction is an allylcopper. 11B NMR studies of
2a + CuF‚3PPh3 suggested the generation of an allylcopper.8
Furthermore, the same enantioselectivity (81-82% ee) was obtained
from 1a using allylboronate 2a, allyltrimethoxysilane, or allyltri-
butylstannane in the presence of CuF-iPr-DuPHOS (15 mol %).
These results strongly suggest that the same active species is
generated through transmetalation, and the highly probable common
i
mol %) and Pr-DuPHOS (4: 30 mol %)10 gave the best enanti-
oselectivity; the product 3a was obtained from acetophenone (1a)
in 42% yield with 79% ee at -40 °C for 20 h in DMF (Table 1,
entry 1). Encouraged by the markedly improved enantioselectivity,
we investigated additive effects, expecting that the addition of a
catalytic amount of Lewis acid metal would improve both reactivity
† The University of Tokyo.
‡ PRESTO.
9
8910
J. AM. CHEM. SOC. 2004, 126, 8910-8911
10.1021/ja047200l CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
% CuF-iPr-DuPHOS as a chiral catalyst and 4.5 mol % La(OiPr)3
as a cocatalyst. The success of the reaction depends on a unique
facilitation effect of La(OiPr)3 in the dynamic ligand exchange
between boron and copper atoms. Detailed mechanistic studies and
application of the present method to other important carbon-carbon
bond-forming reactions are in progress.
Table 2. Catalytic Enantioselective Allylboration of Ketones
Acknowledgment. Financial support was provided by PRESTO
of Japan Science and Technology Corporation (JST).
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 10, p 299. (b) Chemler,
S. R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; Chapter 11, p 403.
(2) For a review, see: Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(3) (a) Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999, 1, 1061.
(b) Cunningham, A.; Woodward, S. Synthesis 2002, 43. (c) Waltz, K.
M.; Gavenonis, J.; Walsh, P. J. Angew. Chem., Int. Ed. 2002, 41, 3697.
(d) Kii, S.; Maruoka, K. Chirality 2003, 15, 67.
(4) For recent selected examples of catalytic enantioselective additions to
simple ketones, see: (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998,
120, 445. (b) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.;
Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 9908. (c) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124,
4233. (d) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544.
(5) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2002, 124, 6536.
a Isolated yield. b Determined by chiral HPLC. c The absolute configu-
ration was determined to be (S).
(6) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586.
(b) Ishiyama, T.; Ahiko, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,
12414. (c) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. J. Am. Chem. Soc.
2003, 125, 10160. (d) Rauniyar, V.; Hall, D. G. J. Am. Chem. Soc. 2004,
126, 4518. (e) Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed.
2003, 42, 4732. For the use of allylboronates in allylation of activated
ketones in the absence of catalyst, see: (f) Pace, R. D.; Kabalka, G. W.
J. Org. Chem. 1995, 60, 4838. (g) Matternich, R.; Hoffmann, R. W.
Tetrahedron. Lett. 1984, 25, 4095.
Table 3. Catalytic Enantioselective Crotylboration of Ketones
(7) Gulliner, D. J.; Levason, W.; Webster, M. Inorg. Chim. Acta 1981, 52,
153. Generation of CuF was observed on 19F NMR via the reaction of
CuCl with TBAT, and CuF is the actual catalyst in our catalytic allylation
using allyltrimethoxysilane. See ref 5.
c
crotylboronate
(1.2 equiv)
time
(h)
yielda
(%)
drb
(syn/anti)
ee
(8) See Supporting Information (SI) for details. No reaction proceeded in the
entry
substrate
(%)
absence of catalyst.
1
2
3
4
1a
1a
1f
2b
2c
2b
2c
1
5
3
4
73
94
80
90
30/70
84/16
27/73
38/62
75/90d
87/74d
90/93
90/92
(9) Brief conclusions of the preliminary optimization: (a) No enantioselectivity
was observed using chiral diamines or monophosphines as a ligand for
Cu. (b) The addition of chiral diphosphines to CuCl-TBAT or CuF‚3PPh3‚
2EtOH produced a less active or less enantioselective catalyst. (c) As a
solvent, DMF is superior to THF in terms of enantioselectivity.
(10) A solution of CuF2‚2H2O and 4 in MeOH was refluxed for 2 h to generate
CuF-4 complex, which was suggested by ESI-MS measurement.
(11) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989.
(12) A dynamic ligand exchange between silicon and copper atoms is the key
for the high reactivity of the previous CuF-catalyzed allylsilylation. See
ref 5. For a review of the coordinating nature of lanthanide metals, see:
Parker, D.; Dickins, R. S.; Puschmann, H.; Crossland, C.; Howard, J. A.
K. Chem. ReV. 2002, 102, 1977.
(13) Other lanthanide isopropoxides gave less satisfactory results.
(14) Even reliable stereoselective allylation methods using chiral allylborane
or allylboronate gave only moderate results when applied to ketones:
Barton’s allyldiisopinocampheylborane and Roush’s tartrate ester-modified
allylboronate gave 3a in 41% yield with 2% ee (0 °C for 2 h) and 16%
yield with 41% ee (-40 °C for 24 h), respectively.
(15) Allylcoppers generated via the reaction of CuX + allyllithium or allyl
Grignard reagent are known to give a mixture of 1,2- and 1,4-adducts to
enones. See: Lipshutz, B. H.; Ellsworth, E.; Dimock, S. H.; Smith, R. A.
J. J. Am. Chem. Soc. 1990, 112, 4404.
(16) On the basis of kinetic studies, the rate-determining step is the generation
of the active nucleophile through a ligand exchange between boron and
copper atoms, and not the addition to a substrate ketone; the initial reaction
rate dependency with regard to CuF‚3PPh3‚2EtOH, 2a, and acetophenone
was 1.4, 1, and 0, respectively.
1f
a Isolated yield. b Determined by NMR. c Determined by chiral HPLC.
d The stereochemistry was determined as shown. Configurations of the
products from 1f were temporarily assigned on the basis of 1H NMR
analysis.
species from these different allylation reagents is an allylcopper.15
Second, in contrast to our initial expectation, the additive effect of
La(OiPr)3 might be due to the acceleration of the transmetalation
step to generate an active allylcopper16 without affecting the
transition-state structure of the allylation step of a substrate ketone.
Thus, the addition of either (R)- or (S)-binaphthoxylanthanum
(generated from La(OiPr)3 and (R)- or (S)-BINOL (1:1) followed
by evaporation of the released PrOH), instead of La(OiPr)3 gave
i
the same enantioselectivity with a slower reaction rate than in the
presence of La(OiPr)3 (Table 1, entries 4 and 5). Further studies
are required to elucidate the origin of the ligand exchange
facilitation effect of La(OiPr)3.17
In conclusion, we have developed the first catalytic enantio-
selective allylboration and crotylboration of ketones using 3 mol
(17) One possible scenario is the activation of CuF through lanthanum
alkoxyfluorocuprate formation.
JA047200L
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J. AM. CHEM. SOC. VOL. 126, NO. 29, 2004 8911