Identification of modular chiral bisphosphines effective for Cu(I)-catalyzed asymmetric allylation and propargylation of ketones

Article abstract of DOI:10.1021/ja101948s

New modular chiral phosphines effective for two distinct Cu(I)-catalyzed asymmetric tetrasubstituted-carbon-forming reactions, namely, allylation and propargylation of ketones, were identified. The optimized phosphine 8 was readily synthesized on a gram scale in high yield via three facile transformations (O-alkylation, bisaminal formation, and phosphination) from commercially available materials. In both reactions, excellent enantioselectivity (up to 98% ee) was produced from a range of substrates, including aromatic and aliphatic ketones, using 0.1-5 mol % catalyst loading. Specifically, catalytic enantioselective propargylation was the first example, affording synthetically useful chiral building blocks that have not been easily accessed to date. In addition to the enantioselectivity, the high catalytic activity of the CuOAc-8 complex is noteworthy. Preliminary studies to elucidate the structure-catalyst activity relationship suggested that the high catalytic activity of the Cu-8 complex is due to the extraordinarily wide bite angle (-P-Cu-P = 137.8°), leading to the stabilization of the active monomeric catalytically active species. Furthermore, mechanistically intriguing nonconventional hydrogen bonds existed between the acetate ligand of Cu and the bisaminal hydrogen atoms, stabilizing the distorted tetrahedral coordination state of the Cu atom.

Full text of DOI:10.1021/ja101948s

Published on Web 04/26/2010
Identification of Modular Chiral Bisphosphines Effective for Cu(I)-Catalyzed
Asymmetric Allylation and Propargylation of Ketones
Shi-Liang Shi,† Li-Wen Xu,† Kounosuke Oisaki,† Motomu Kanai,*,† and Masakatsu Shibasaki*,†,‡
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received March 8, 2010; E-mail: kanai@mol.f.u-tokyo.ac.jp; mshibasa@bikaken.or.jp
Chiral phosphines play pivotal roles in asymmetric catalysis.1 Many
Scheme 1. Systematic Optimization of the Modular Ligand
privileged chiral phosphines have been developed. Continuous structural
improvement and diversification are still necessary, however, to achieve
high asymmetric induction in difficult-to-control C-C bond formations,
such as construction of tetrasubstituted carbons.2 Synthesis of chiral
phosphines is generally labor-intensive, which has hampered their intensive
structural optimization. A modular approach would facilitate chiral
phosphine development, as it would allow for rapid and systematic
synthesis of molecules with structurally diverse arrays.3 We report herein
the discovery of new modular chiral phosphines that produce excellent
enantioselectivity in Cu(I)-catalyzed asymmetric allylation and propargy-
lation of ketones.
a Enantiomeric excess and yield of 3a. b (S)-3a was obtained. c Using 2
We previously reported an asymmetric allylboration of ketones
i
mol % catalyst at -75 °C in the presence of 1 equiv of PrOH.
using a catalytic combination of a CuX-iPr-DuPHOS complex (X
) F, OR) and hard-metal (La, Li, K) alkoxides.4,5 The active
Table 1. Catalytic Asymmetric Allylation of Ketonesa
nucleophile was an allylcopper species generated through trans-
metalation of an allylboronate.6 Although the products were
obtained in high yield, the enantioselectivity was not necessarily
satisfactory, even after intensive screening of commercially available
chiral phosphines. For example, product 3a from acetophenone (1a)
was produced in 94% yield with 82% ee. To improve the
enantioselectivity, we started a program to develop chiral phosphine
ligands with a completely new scaffold. Our basic ligand design
concept was to construct chiral phosphines through the facile
assembly of independent modules.
We first synthesized diphosphine 4 via bisaminal formation using
an air-stable triarylphosphine module and an inexpensive chirality-
introducing aminodiol. Its function was assessed by Cu-catalyzed
asymmetric allylation of 1a (Scheme 1). Despite the simple and
flexible structure of 4, a CuOAc-4 complex7 produced (R)-3a in
quantitative yield with a promising 41% ee. To improve the
enantioselectivity, we designed 5 containing a conformationally
constrained 13-membered macrocycle. Ligand 5 comprised four
a Standard conditions are shown in the scheme. Isolated yields and
enantiomeric excesses determined by chiral HPLC or GC are
summarized. b Using 0.1 mol % CuOAc and 0.12 mol % 8. c At -60
modules (linker, wing, chiral head, and phosphine) and was
synthesized on a gram scale in three steps from commercially
available starting materials (overall yield 70%).8 As expected, the
use of 5 improved the enantioselectivity to 76% ee.
d
°C. Using 5 mol % CuOAc and 6 mol % 8 with 1 equiv of LiOiPr at
-60 °C. e The absolute configuration was determined as shown.
The effects of the structural modification of each module of 5
were then systematically investigated.8 Four significant trends were
observed (Scheme 1): (1) As a substituent of the chiral head (R),
aromatic groups were essential (5 vs 6). (2) The chirality of C2
had almost no effect on the enantioselectivity (5 vs 7). (3) A specific
rigid conformation of the core macrocycle defined by the linker
and wing modules was critical.8 (4) Introduction of electron-
withdrawing substituents at the para position of the phosphine part
(Ar) improved the enantioselectivity (5 vs 8). Addition of 1 equiv
of iPrOH effectively enhanced the reactivity,5f,l allowing the reaction
temperature to be decreased to -75 °C; product 3a was obtained
with 89% ee using 2 mol % catalyst.
The substrate scope was then studied under the optimized
conditions (Table 1). In general, the enantioselectivity and catalytic
activity were significantly higher than in our previous reaction using
iPr-DuPHOS.4,9 The crotylation reaction also proceeded with
improved diastereo- and enantioselectivity (3m and 3n). In
comparison with the organocatalyzed reaction recently reported by
Schaus,5l the enantio- and diastereoselectivity were slightly inferior.
The high catalytic activity and applicability to saturated aliphatic
ketones (e.g., 1l), however, are advantages of our reaction. In an
ideal case, the catalyst loading was reduced to 0.1 mol % (3h).
To expand the utility of ligand 8, we applied the CuOAc-8
catalyst to an enantioselective propargylation of ketones10 using
allenylboronate 9 (Table 2). Homopropargyl tertiary alcohols 10
† The University of Tokyo.
‡ Present address: Institute of Microbial Chemistry, Tokyo.
9
6638 J. AM. CHEM. SOC. 2010, 132, 6638–6639
10.1021/ja101948s  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric Propargylation of Ketonesa
Acknowledgment. Financial support was provided by a Grant-
in-Aid for Young Scientists (S) from JSPS. L.-W.X. and K.O. thank
JSPS for research fellowships.
Supporting Information Available: Experimental procedures,
characterization of the products, ligand optimization, and theoretical
support for the nonconventional hydrogen bonding. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Phosphorus Ligands in Asymmetric Catalysis; Bo¨rner, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2008.
(2) (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Riant, O.; Hannedouche,
J. Org. Biomol. Chem. 2007, 5, 873. (c) Hatano, M.; Ishihara, K. Synthesis
2008, 1647.
(3) For examples, see: (a) Reetz, M.; Mehler, G. Angew. Chem., Int. Ed. 2000,
39, 3889. (b) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch,
J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2000, 122, 11539. (c) Clark, T. P.; Landis, C. R. J. Am. Chem. Soc. 2003,
125, 11792. (d) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe,
T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (e) Takacs,
J. M.; Reddy, D. S.; Moteki, S. A.; Wu, D.; Palencia, H. J. Am. Chem.
Soc. 2004, 126, 4494. (f) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall,
J. J. Am. Chem. Soc. 2006, 128, 3922. (g) Weis, M.; Waloch, C.; Seiche,
W.; Breit, B. J. Am. Chem. Soc. 2006, 128, 4188. (h) Liu, Y.; Sandoval,
C. A.; Yamaguchi, Y.; Zhang, X.; Wang, Z.; Kato, K.; Ding, K. J. Am.
Chem. Soc. 2006, 128, 14212. (i) Hattori, G.; Hori, T.; Miyake, Y.;
Nishibayashi, Y. J. Am. Chem. Soc. 2007, 129, 12930. (j) Wakabayashi,
K.; Aikawa, K.; Kawauchi, S.; Mikami, K. J. Am. Chem. Soc. 2008, 130,
5012. (k) Yu, J.; RajanBabu, T. V.; Parquette, J. R. J. Am. Chem. Soc.
2008, 130, 7845. (l) Patureau, F. W.; de Boer, S.; Kuil, M.; Meeuwissen,
J.; Breuil, P. R.; Siegler, M. A.; Spek, A. L.; Sandee, A. J.; de Bruin, B.;
Reek, J. N. H. J. Am. Chem. Soc. 2009, 131, 6683.
a Standard conditions are shown in the scheme. Isolated yields and
enantiomeric excesses determined by chiral HPLC are summarized.
b Using 5 mol % catalyst. c The absolute configuration was determined
as shown.
(4) (a) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8910. (b) Kanai, M.; Wada, R.; Shibuguchi, T.; Shibasaki, M.
Pure Appl. Chem. 2008, 80, 1055.
(5) For other examples of catalytic asymmetric allylation of ketones, see: (a)
Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999, 1, 1061. (b)
Hanawa, H.; Kii, S.; Maruoka, K. AdV. Synth. Catal. 2001, 343, 57. (c)
Cunningham, A.; Woodward, S. Synlett 2002, 43. (d) Waltz, K. M.;
Gavenonis, J.; Walsh, P. J. Angew. Chem., Int. Ed. 2002, 41, 3697. (e)
Teo, Y.-C.; Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743. (f) Wadamoto,
M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556. (g) Lou, S.;
Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660. (h)
Zhang, X.; Chen, D.; Liu, X.; Feng, X. J. Org. Chem. 2007, 72, 5227. (i)
Miller, J. J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752. (j)
Schneider, U.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130,
13824. (k) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int. Ed. 2009,
48, 6313. (l) Barnett, D. S.; Moquist, P. N.; Schaus, S. E. Angew. Chem.,
Int. Ed. 2009, 48, 8679. (m) Huang, X.-R.; Chen, C.; Lee, G.-H.; Peng,
S.-M. AdV. Synth. Catal. 2009, 351, 3089.
Figure 1. (a) X-ray crystal structure of the CuOAc ·H2O-8 complex. (b)
Its chemical description.
were produced with high enantioselectivity from a range of ketones.
The reaction proceeded with perfect regioselectivity (γ-addition),
and the corresponding allenyl alcohol isomers (R-adducts) were
not detected in any case. Because of the synthetic versatility of
terminal alkynes, various product conversions, such as Sonogashira
coupling and one-pot Huisgen cycloaddition with azides (using the
same Cu catalyst),11 were possible.8 Therefore, this reaction
produces a synthetically independent family of chiral building
blocks for allylation. To our knowledge, this is the first catalytic
enantioselective propargylation of ketones.
To gain preliminary insight into the origin of the high catalytic
activity and enantioselectivity of the CuOAc-8 complex, we
elucidated the X-ray crystal structure of the complex (Figure 1).12
The central 13-membered macrocycle forms a conformationally
rigid folded structure in which the linker aromatic group overhangs
the chiral bisaminal bicyclo[3.3.0] system. The observed bite angle
is extraordinarily wide (∠P-Cu-P ) 137.8°), resulting in the
stabilization of the catalytically active monomeric Cu complex.8,13
In addition, the oxygen atom of the acetate ligand forms noncon-
ventional C-H· · ·O hydrogen bonds with the bisaminal protons,14
leading to a distortion of the tetrahedral geometry around the copper
atom. The relevance of this distorted geometry and hydrogen-
bonding ability to the enantioselectivity and high catalytic activity
is currently under investigation.
(6) Russo, V.; Herron, J. R.; Ball, Z. T. Org. Lett. 2010, 12, 220.
(7) Cu(I) salts conjugated with a hard anion (e.g., F-, RO-, RCO2-) generally
promoted the allylation reaction without affecting the enantioselectivity.
Preparation of the asymmetric catalyst was simpler using CuOAc (simple
mixing with an approximately equimolar amount of the chiral phosphine)
than CuF [reduction of CuF2 using 2 equiv of the chiral phosphine relative
to Cu (see ref 4a)]. The catalytic activity of CuF, however, was generally
higher than that of CuOAc.
(8) See the Supporting Information (SI) for details.
(9) When iPr-DuPHOS and xantphos were used under the current optimized conditions,
the product yields were markedly lower (less than 5% for 1a) than when 8 was
used. Moreover, no detectable amount of product was obtained in propargylation
using CuOAc-iPr-DuPHOS or -xantphos catalyst.
(10) Enantioselective propargylation of ketones depended on the use of
stoichiometric amounts of chiral sources. See: (a) Justicia, J.; Sancho-Sanz,
´
I.; Alvarez-Manzaneda, E.; Oltra, J. E.; Cuerva, J. M. AdV. Synth. Catal.
2009, 351, 2295. (b) Hernandez, E.; Burgos, C. H.; Alicea, E.; Soderquist,
J. A. Org. Lett. 2006, 8, 4089.
(11) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004.
(12) Use of the crystal as an asymmetric catalyst produced results comparable
to those for the in situ-prepared CuOAc-8 complex.
(13) (a) A clear dependence of the catalytic activity on the aggregation state of
the Cu-bisphosphine (8, iPr-DuPHOS, xantphos) complexes was observed
(see the SI for details). (b) Sterically bulky phosphines markedly enhance
the reactivity of Cu-catalyzed hydrosilylation reactions by stabilizing active
monomeric catalysts. For examples, see: Deutsch, C.; Krause, N.; Lipshutz,
B. H. Chem. ReV. 2008, 108, 2916.
(14) For examples of C-H · · · O hydrogen bonding, see: (a) Vargas, R.; Garza,
J.; Dixon, D. A.; Hay, B. P. J. Am. Chem. Soc. 2000, 122, 4750. (b) Corey,
E. J.; Lee, T. W. Chem. Commun. 2001, 1321. (c) C-H · · · O hydrogen-
bond formation in the CuOAc-8 complex was also supported by density
functional theory calculations (see the SI). (d) The crystal structure of the
CuOAc-5 complex did not contain H2O, but the C-H· · ·O hydrogen bond
still existed (see the SI).
In conclusion, we have identified new modular chiral phosphines
that are effective for Cu(I)-catalyzed asymmetric allylation and
propargylation of ketones. Studies directed toward obtaining a more
detailed understanding of the enantiodifferentiation mechanism and
extending the utility of the new phosphines to other catalytic
asymmetric reactions are in progress.
JA101948S
9
J. AM. CHEM. SOC. VOL. 132, NO. 19, 2010 6639