Copper(I)-secondary diamine complex-catalyzed enantioselective conjugate boration of linear β,β-disubstituted enones

Article abstract of DOI:10.1021/ol101691p

A copper(I)-chiral secondary diamine (L-e) complex catalyzes an enantioselective conjugate boration of β,β-disubstituted enones in high yields and up to 99% ee. Product chiral tertiary organoboronates can be converted to enantiomerically enriched cross-aldol products between ketones without any racemization.

Full text of DOI:10.1021/ol101691p

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4098-4101
Copper(I)-Secondary Diamine
Complex-Catalyzed Enantioselective
Conjugate Boration of Linear
ꢀ,ꢀ-Disubstituted Enones
I-Hon Chen,† Motomu Kanai,*,‡ and Masakatsu Shibasaki*,†
Institute of Microbial Chemistry, Tokyo, Kamiosaki 3-14-23, Shinagawa-ku,
Tokyo 141-0021, Japan, and Graduate School of Pharmaceutical Sciences,
The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
kanai@mol.f.u-tokyo.ac.jp; mshibasa@bikaken.or.jp
Received July 21, 2010
ABSTRACT
A copper(I)-chiral secondary diamine (L-e) complex catalyzes an enantioselective conjugate boration of ꢀ,ꢀ-disubstituted enones in high
yields and up to 99% ee. Product chiral tertiary organoboronates can be converted to enantiomerically enriched cross-aldol products between
ketones without any racemization.
Catalytic asymmetric conjugate addition is a fundamentally
important method in organic synthesis.1 Various reactions
in this category have been developed using ꢀ-monosubsti-
tuted R,ꢀ-unsaturated carbonyl substrates. A variant using
ꢀ,ꢀ-disubstituted substrates to construct chiral ꢀ-tetrasubsti-
tuted carbons, however, is still difficult to accomplish.2 This
is due both to the lower reactivity and smaller steric and
electronic differences between two substituents on prochiral
carbons of substrates for tetrasubstituted carbon construction,
compared to those for tertiary carbon construction.
especially interested in the conjugate boration3 of ꢀ,ꢀ-
disubstituted R,ꢀ-unsaturated carbonyl substrates. Chiral
organoboron compounds4 are versatile synthetic intermedi-
ates because C-B bonds can be converted to various
functional groups.5 Furthermore, R-chiral organoboron mol-
ecules exhibiting unique biological activities were identified,
(2) For examples, see: (a) Hird, A. W.; Hoveyda, A. H. J. Am. Chem.
Soc. 2005, 127, 14988. (b) d’Augustin, M.; Palais, L.; Alexakis, A. J. Angew.
Chem., Int. Ed. 2005, 44, 1376. (c) Lee, K.; Brown, M. K.; Hird, A. W.;
Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182. (d) Fillion, E.; Wilsily,
A. J. Am. Chem. Soc. 2006, 128, 2774. (e) Brown, M. B.; May, T. L.;
Baxter, C. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 1097. (f)
Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi, T. J. Am.
Chem. Soc. 2009, 131, 13588. (g) Matsumoto, Y.; Yamada, K.; Tomioka,
K. J. Org. Chem. 2008, 73, 4578. (h) May, T.; Brown, M. K.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2008, 47, 7358. (i) Hawner, C.; Li, K.; Cirriez,
V.; Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 8211. (j) Wilsily, A.;
Fillion, E. Org. Lett. 2008, 10, 2801. (k) Shintani, R.; Isobe, S.; Takeda,
M.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3795. (l) Mazet, C.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2008, 47, 1762. (m) Tanaka, Y.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 8862.
Among several candidate reactions for the catalytic enan-
tioselective construction of ꢀ-tetrasubstituted carbons, we are
† Institute of Microbial Chemistry.
‡ The University of Tokyo.
(1) (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Cozzi, P. G.;
Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 36, 5969. (c)
Alexakis, A.; Ba¨ckvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem.
ReV. 2008, 108, 2796. (d) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnard, A. J.; Feringa, B. L. Chem. ReV. 2008, 108, 2824.
10.1021/ol101691p  2010 American Chemical Society
Published on Web 08/19/2010

such as potent inhibitors of the proteasome, thrombin, and
histone deacetylases.6
Table 1. Optimization of Reaction Conditions
We previously developed the catalytic enantioselective
conjugate boration of cyclic ꢀ-substituted enones using a
catalyst prepared from CuPF6(CH3CN)4 modified by Qui-
noxP*7 and LiOtBu, bis(pinacolato)diboron (PinBBPin) as
a borylating reagent, and DMSO as a solvent.8 Due to the
importance of R-chiral organoboron compounds, we wanted
to expand the substrate scope further to linear ꢀ,ꢀ-disubsti-
tuted enones. Identifying remarkable ligand effects, we report
herein a catalytic enantioselective boration of linear ꢀ,ꢀ-
disubstituted enones.
We first applied the previously optimized reaction condi-
tions for cyclic enones to the model substrate (E)-4-
phenylpent-3-en-2-one (1a) (Table 1, entry 1). The desired
product 2a was obtained in excellent yield; however,
enantioselectivity was only moderate (38% ee). After com-
prehensive screening of various chiral phosphine ligands, the
enantioselectivity was still unsatisfactory.9 Therefore, we
turned our attention to the use of chiral amine ligands.
Despite several advantages of chiral amine ligands to
phosphine ligands (such as high stability toward oxidation,
low cost, and easy tunability), there were few efficient
asymmetric reactions to date using a nucleophilic Cu(I)-chiral
amine complex as a catalyst.10 This is likely due to the
weaker affinity of amine ligands for Cu(I) compared to
phosphine ligands. Because the target reaction was a ligand-
accelerated process and no reaction proceeded in the absence
a Isolated yield. b Determined by chiral HPLC. c The reaction was run
in the presence of i-PrOH (2 equiv). d Slow addition of i-PrOH for 12 h.
(3) (a) Mun, S.; Lee, J.; Yun, J. Org. Lett. 2006, 8, 4887. (b) Lee, J.;
Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145. (c) Sim, H.; Feng, X.; Yun,
J. Chem.sEur. J. 2009, 15, 1939. (d) Chea, H.; Sim, H.; Yun, J. AdV. Synth.
Catal. 2009, 351, 855. (e) Lillo, V.; Prieto, A.; Bonet, A.; D´ıaz-Requejo,
M. M.; Ram´ırez, J.; Pe´rez, P. J.; Ferna´ndez, E. Organometallics 2009, 28,
659. (f) Fleming, W. J.; Mu¨ller-Bunz, H.; Lillo, V.; Ferna´ndez, E.; Guiry,
P. J. Org. Biomol. Chem. 2009, 7, 2520. (g) Schiffner, J. A.; Mu¨ther, K.;
Oestreich, M. Angew. Chem., Int. Ed. 2010, 49, 1194. (h) Bonet, A.; Gulya´s,
H.; Ferna´ndez, E. Angew. Chem., Int. Ed. 2010, 49, 5130. (i) During the
preparation of this manuscript, Hoveyda’s group reported the catalytic
enantioselective conjugate boration of linear ꢀ,ꢀ-disubstituted R,ꢀ-unsatur-
ated carbonyl compounds. See: O’Brien, J. M.; Lee, K.; Hoveyda, A. H.
J. Am. Chem. Soc. 2010, 132, 10630.
of ligand, we speculated that even dative chiral amine ligands
could induce high enantioselectivity.
As expected, the reaction still proceeded using bisoxazo-
line-type ligands; however, the enantioselectivity was low
(Table 1, entries 2 and 3). The use of ligand L-c with a 1,2-
cyclohexanediamine scaffold afforded 2a in good yield with
moderate enantioselectivity (31% ee; entry 4). The use of
ligand L-d containing a 1,2-diphenylethylenediamine skel-
eton afforded better results, and 2a was obtained in 90%
yield with 53% ee (entry 5).11 At this stage, solvent effects
were examined and 1,2-dimethoxyethane (DME) was the
optimum solvent with enantioselectivity improved to 85%
ee without affecting the reactivity (entry 6).9 Further
structural tuning of the chiral ligand was examined using
DME as a solvent. The use of ligand L-e containing N-ethyl
substituents produced 2a with 93% ee; however, the yield
decreased to 54% (entry 7). Increasing the steric nature of
the ligand nitrogen substituents dramatically decreased the
reactivity (L-f; entry 8).
(4) For other examples of the catalytic asymmetric synthesis of chiral
organoboron compounds (hydroboration and diboration), see: (a) Lee, Y.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160. (b) Smith, S. M.;
Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734. (c)
Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125,
8702. (d) Burks, H. E.; Morken, J. P. Chem. Commun. 2007, 4717. (e) Ito,
H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc.
2007, 129, 14856. (f) Burks, H. E.; Kliman, L. T.; Morken, J. P. J. Am.
Chem. Soc. 2009, 131, 9134. (g) Kliman, L. T.; Mlynarski, S. N.; Morken,
J. P. J. Am. Chem. Soc. 2009, 131, 13210. (h) Guzman-Martinez, A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10634.
(5) For example, see: (a) Hupe, E.; Marek, I.; Knochel, P. Org. Lett.
2002, 4, 2861. (b) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M.
Tetrahedron Lett. 1989, 30, 1483. (c) Matteson, D. S. Tetrahedron 1998,
54, 10555. (d) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778. (e) Imao, D.; Glasspoole, B. W.; Laberge, V. S.;
Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024. (f) Ros, A.; Aggarwal,
V. K. Angew. Chem., Int. Ed. 2009, 48, 6289. (g) Bagutsu, V.; French,
R. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2010, 49, 5142.
(6) (a) Kane, R. C.; Bross, P. F.; Farrell, A. T.; Pazdur, R. Oncologist
2003, 8, 508. (b) Kettner, C.; Mersinger, L.; Knabb, R. J. Biol. Chem. 1990,
265, 18289. (c) Suzuki, N.; Suzuki, T.; Ota, Y.; Nakano, T.; Kurihara, M.;
Okuda, H.; Yamori, T.; Tsumoto, H.; Nakagawa, H.; Miyata, N. J. Med.
Chem. 2009, 52, 2909.
To improve the reactivity, several additives were next
examined using L-e as the ligand. Although phosphine oxide
(10) Cu(I)-chiral arylamine complexes are used as catalytst, see: ref 2a
and: (a) Hatano, M.; Asai, T.; Ishihara, K. Tetrahedron Lett. 2008, 49, 379.
(b) Orlandi, S.; Colombo, F.; Benaglia, M. Synthesis 2005, 1689. Lewis
acidic Cu(II)-chiral amine complexes are excellent asymmetric catalysts
for various reactions; see: (c) Evans, D. A.; Tregay, S. W.; Burgey, C. S.;
Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936. (d)
Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M.
J. Am. Chem. Soc. 2003, 125, 2507. (e) Johannsen, M.; Jørgensen, K. A. J.
Org. Chem. 1995, 60, 5757.
(7) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127,
11934.
(8) Chen, I.-H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 11664.
(11) Only a trace amount of 2a was produced in the absence of copper
(in the presence of t-BuOLi and L-d).
(9) See the Supporting Information.
Org. Lett., Vol. 12, No. 18, 2010
4099

additives, previously identified as an accelerator in a related
Cu(I) catalysis,12 proved to give less satisfactory results,
addition of 2 equiv of PrOH markedly improved the yield
without affecting the excellent enantioselectivity (entry 9).13
No further improvement was observed with the slow addition
of 2-propanol (entry 10). Interestingly, chiral tertiary-diamine
ligand L-g without NH groups afforded dramatically de-
creased enantioselectivity (entry 11), suggesting that the NH
group had a profound role in enantio-induction (see below).
using chiral copper(I) catalysts,15 were competent as well
(entries 8-12). The products were obtained both from (E)-
and (Z)-substrates in comparably high, but opposing, enan-
tioselectivities (entries 9-12). This result is also noteworthy
because (E)- and (Z)-substrates are completely different
substrates for asymmetric catalysts in a general sense.4e
Due to the synthetic versatility of organoboron compounds,
a variety of synthetically useful conversions of the products
are conceivably possible. Here we demonstrate a typical
example (eq 1). Boronate 2a was converted to chiral
ꢀ-hydroxy ketone 3a in high yield without any racemization
through oxidation of 2a with sodium perborate, and the same
conditions could be applied in the oxidation of aliphatic chiral
boronate to afford the corresponding product, 3g.5b Enan-
tiomerically enriched ꢀ-hydroxy ketones 3a and 3g are cross
aldol-type products between ketones. There is no report of
catalytic asymmetric aldol reaction to ketones using ketone-
derived nucleophiles to date.16
i
The substrate generality of this asymmetric conjugate
boration of linear ꢀ,ꢀ-disubstituted enones is summarized
in Table 2. Products derived from ꢀ-aromatic-substituted
Table 2. Catalytic Enantioselective Conjugate Boration of
ꢀ,ꢀ-Disubstituted Enones
entry
substrate: R1, R2
yielda (%)
eeb (%)
To gain preliminary insight into the reaction mechanism,
including the critical role of the NH group of the chiral
ligand,17 we performed the following experiments. The first
fundamental mechanistic question is whether the chiral
diamine ligand coordinates to the lithium atom of LiPF6 or
the copper atom of CuB(Pin) when the enantioselective
conjugate boration proceeds.18 To answer this question, we
examined a reaction under Li-free CuO-t-Bu19-L-e system.
As a result, product 2a was obtained in 89% yield with 92%
ee. This result clearly indicates that the diamine coordinates
to the copper atom at the enantio-differentiating step even
in the presence of the cationic lithium atom.
1
1a: Me, (E)-Ph
1a: Me, (E)-Ph
86
80
87
87
71
91
80
87
95
93
80
83
92d
90d
92
95
96
93
96
94
94
96
94
99
2c
3
1b: Me, (E)-p-tolyl
1c: Me, (E)-m-tolyl
1d: Me, (E)-3-Cl-C6H4
1e: Me, (E)-3-F-C6H4
1f: Et, (E)-Ph
1 g: Me, (E)-(CH2)2Ph
1 h: Ph(CH2)2, (E)-Bu
1i: Ph(CH2)2, (Z)-Bu
1j: c-Hex, (E)-Bu
1k: c-Hex, (Z)-Bu
4
5
6
7
8
9
10e
11
12f
a Isolated yield. b Determined by chiral HPLC. c 5 mol % of catalyst.
d Absolute configuration of the product was determined as shown in eq 1.
e The enantiomer of the product obtained in entry 9 was produced. f The
enantiomer of the product obtained in entry 11 was produced.
(15) Only a limited number of examples giving high enantioselectivity
in catalytic conjugate addition to linear ꢀ,ꢀ-dialkyl-substituted enones as
the substrates were published. See refs 2f (Rh catalyst), 2l (Al catalyst),
2m (Sr catalyst), and 3i (Cu catalyst).
(16) For examples of catalytic asymmetric aldol reactions of ketones
using ester enolates, see: (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc.
2002, 124, 4233. (b) Moreau, X.; Bazan-Tejeda, B.; Campagne, J.-M. J. Am.
Chem. Soc. 2005, 127, 7288. (c) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 7164. (d) Deschamp, J.; Chuzel, O.;
Hannedouche, J.; Riant, O. Angew. Chem., Int. Ed. 2006, 45, 1292. (e)
Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 14440. (f) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 7439.
enones were obtained in high yield and excellent enantiose-
lectivity (entries 1-7). Catalyst loading was reduced to 5
mol % in an ideal case (entry 2). In addition to methyl-
substituted enones, linear and branched alkyl-substituted
enones also produced excellent results (entries 7-12).14 ꢀ,ꢀ-
Dialkyl-substituted enones, generally quite challenging acy-
clic substrates for asymmetric conjugate addition reactions
(17) For examples of asymmetric catalysis using secondary amine-
derived ligands, see: (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya,
T.; Noyrori, R. Angew. Chem., Int. Ed. 1997, 36, 285. (b) Yamakawa, M.;
Ito, H.; Noyrori, R. J. Am. Chem. Soc. 2000, 122, 1466. (c) Tobe, M. L.
AdV. Inorg. Bioinorg. Mech. 1983, 2, 1. (d) Egami, H.; Oguma, T.; Katsuki,
T. J. Am. Chem. Soc. 2010, 132, 5886. (e) Matsumoto, K.; Sawada, Y.;
Saito, B.; Sakai, K.; Katsuki, T. Angew. Chem., Int. Ed. 2005, 44, 4935. (f)
Nakamura, A.; Lectard, S.; Hashizume, D.; Hamashima, Y.; Sodeoka, M.
J. Am. Chem. Soc. 2010, 132, 4036. (g) Dai, X.; Strotman, N. A.; Fu, G. C.
J. Am. Chem. Soc. 2008, 130, 3302. (h) Saito, B.; Fu, G. C. J. Am. Chem.
Soc. 2008, 130, 6694.
(12) (a) Chen, I.-H.; Oisaki, K.; Kanai, M.; Shibasaki, M. Org. Lett.
2008, 10, 5151. (b) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2010, 132, 5522.
(13) The dramatic acceleration of the reaction rate by the addition of
MeOH in the catalytic enantioselective conjugate boration was originally
reported by Yun (ref 3a-d). In our present reaction, however, addition of
MeOH did not improve the yield (43% yield with 90% ee vs 86% yield
with 92% ee using i-PrOH; Table 1, entry 9).
(18) For a DFT calculation study of Cu-phosphine complex-catalyzed
conjugate boration, see: Dang, L.; Lin, Z.; Marder, T. B. Organometallics
2008, 27, 4443.
(19) (a) Tsuda, T.; Hashimoto, T.; Saegusa, T. J. Am. Chem. Soc. 1972,
94, 658. (b) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki,
M. Org. Lett. 2003, 5, 3147.
(14) R,ꢀ-Unsaturated esters were not reactive under the current condi-
tions. Phenyl ketones produced mixtures of many unidentified products.
4100
Org. Lett., Vol. 12, No. 18, 2010

ESI-MS experiments were then conducted to gain infor-
mation about the intermediates in the catalytic cycle. A Cu+/
L-e ) 1:1 complex (4) was observed as a sole species in a
mixture of L-e ligand and CuPF6·4CH3CN. A new peak
corresponding to 5 (Figure 1) then emerged [MW ) 892
Scheme 1. Proposed Catalytic Cycle
Figure 1. Chiral secondary diamine-copper(I) complex 4 and
borylated diamine ligand-copper(I) complex 5.
(m/z)] again as a sole peak under cation-mode observation
when t-BuOLi and (Pin)BB(Pin) were added to 4.9,20
This observation suggested that a copper amide species
6-e might be generated from 4 and LiO-t-Bu, and the
copper-nitrogen bond cleaves (Pin)BB(Pin) through me-
tathesis, generating copper boronate complex 7 containing
an N-borylated ligand. To provide support for this hypothesis,
we prepared copper amide complexes 6 from CuPF6·4CH3CN
and lithium amides derived from L-d and L-e, respectively,
and used 6 as enantioselective catalysts (eq 2). Product 2a
was produced with comparable enantioselectivities to that
obtained under CuPF6·4CH3CN-LiO-t-Bu-L-d and -L-e
systems (cf. Table 1, entry 6 and 9).21
of the aminopinacolyl boronate part of the catalyst, generat-
ing a pretransition state complex 8.22 Enantioselective
conjugate boration from 8 would produce boron enolate
complex 9 (or a copper enolate complex, alternatively),
which would be protonated by 2-propanol,23 and reactive
species 7 would be regenerated by reaction with (Pin)-
BB(Pin). This proposed mechanism is in accordance with
the low enantioselectivity observed when using diamine
ligands without an ability to form copper amides (L-a,b,g).
In conclusion, we have developed a catalytic enantiose-
lective conjugate boration of linear ꢀ,ꢀ-disubstituted enones
by identifying the copper(I)-secondary-diamine L-e catalytic
system. Products were converted to ketone-ketone cross
aldol-type compounds in excellent yields without any race-
mization. Considering the facile structural tunability of amine
ligands, this study might provide a foundation for developing
further chiral amine-transition-metal-catalyzed enantiose-
lective reactions. More detailed mechanistic studies are
currently ongoing.
Based on these results, we proposed a working hypothesis
for the catalytic cycle as shown in Scheme 1. After generation
of borylcopper species 7 either through metathesis between
copper amide and (Pin)BB(Pin) or CuO-t-Bu and (Pin)BB-
(Pin) followed by N-boration, the carbonyl oxygen atom of
the substrate might coordinate to the Lewis acidic boron atom
Acknowledgment. Financial support was provided by
Grant-in-Aid for Scientific Research (S) from JSPS. We
thank Mr. S. Ito at The University of Tokyo for partial
contribution to this work.
Supporting Information Available: Experimental pro-
cedure, characterization data, MS analysis of catalytic
intermediates, and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Complex 5 would be formed via dissociation of the N-borylated
L-e from a copper atom of complex 7, re-association to another 7, and
ionization in the ESI-MS apparatus by eliminating (Pin)B- from the copper
atom.
(21) The result of the reaction using 6-d in the absence of iPrOH indicates
that a copper amide can, at least, activate (Pin)BB(Pin) through N-boration.
However, we cannot exclude the involvment of a pathway starting from
CuOtBu and without N-boration under the optimized conditions (Table 2),
because the product yield was not comparable when using 6 instead of
OL101691P
(22) Molecular modeling study indicated that the Cu-B σ bond can
overlap with the enone π* orbital in 8.
(23) In the absence of 2-propanol, the boron enolate liberated from 9
should be the product in the reaction mixture (Table 1, entry 6).
t
CuPF6 + BuOK. More direct observation of proposed 8 awaits further
studies.
Org. Lett., Vol. 12, No. 18, 2010
4101