Catalytic asymmetric conjugate addition of α-cyanoketones for the construction of a quaternary stereogenic center

Article abstract of DOI:10.1021/ol100183s

(Figure Presented) The catalytic asymmetric conjugate addition of a-cyanoketone pronucleophiles to vinyl ketones promoted by a Y/1 catalyst is described. High enantioselectivity was observed for a range of aromatic vinyl ketones, providing 1,5-dicarbonyl compounds bearing an all-carbon quaternary stereogenic center. The product was successfully converted to a spiro-piperidine entity and a bicyclo[3.3.0]octane framework through either the reduction of nitrile or intramolecular pinacol coupling.

Full text of DOI:10.1021/ol100183s

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1484-1487
Catalytic Asymmetric Conjugate
Addition of r-Cyanoketones for the
Construction of a Quaternary
Stereogenic Center
Yuji Kawato, Noriko Takahashi, Naoya Kumagai,* 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; nkumagai@mol.f.u-tokyo.ac.jp
Received January 25, 2010
ABSTRACT
The catalytic asymmetric conjugate addition of r-cyanoketone pronucleophiles to vinyl ketones promoted by a Y/1 catalyst is described. High
enantioselectivity was observed for a range of aromatic vinyl ketones, providing 1,5-dicarbonyl compounds bearing an all-carbon quaternary
stereogenic center. The product was successfully converted to a spiro-piperidine entity and a bicyclo[3.3.0]octane framework through either
the reduction of nitrile or intramolecular pinacol coupling.
The construction of highly functionalized organic molecules
containing an all-carbon quaternary chiral center by asym-
metric catalysis remains a formidable task in modern organic
synthesis.1 Recent advances in this field revealed that the
catalytic asymmetric conjugate addition of active methine
pronucleophiles to electron-deficient alkenes is a highly
versatile strategy for producing this class of compounds
bearing functional groups that are amenable to subsequent
manipulation.2 Extensive studies have been devoted to the
development of asymmetric conjugate addition using R-sub-
stituted ꢀ-dicarbonyl compounds as pronucleophiles for the
construction of an all-carbon quaternary stereogenic center;3
however, related transformations using R-cyanocarbonyl
compounds have been less explored.4,5 The rich chemistry
of functional group interconversion of nitriles allows for the
elaboration of the conjugate addition products. Previously,
we reported that a rare earth metal (RE)/amide-based ligand
1 catalytic system is quite effective for a catalytic asymmetric
Mannich-type reaction of R-cyanoketones 2 with switchable
diastereoselection depending on the choice of RE.6 In our
continuing efforts to expand the utility of the RE/1 catalytic
system,7-9 we applied the RE/1 catalyst to the asymmetric
conjugate addition of R-cyanoketones 2 to vinyl ketones 3,
affording 1,5-dicarbonyl compounds bearing an all-carbon
Scheme 1
.
Catalytic Asymmetric Conjugate Addition of
R-Cyanoketones
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4591. (c) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363. (d) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
10.1021/ol100183s  2010 American Chemical Society
Published on Web 03/04/2010

quaternary stereogenic center (Scheme 1). Facile transforma-
tion allowed for access to enantioenriched spiro-piperidine
and bicyclo[3.3.0]octane entities.
Table 1. Catalytic Asymmetric Conjugate Addition of
R-Cyanoketones Promoted by a RE/1 catalysta
time
(h)
yieldb
(%)
eec
(%)
entry
RE
x
solvent
config
1
2
3
4
5
6
7
8
Sc
Y
10
10
10
10
10
10
10
10
10
10
10
10
5
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
THF
24
24
24
24
24
24
24
24
24
24
24
24
24
18
81
90
96
80
86
86
37
88
81
83
88
89
2
77
28
24
4
26
9
14
12
1
R
R
S
S
S
R
R
S
R
R
R
R
R
Figure 1. CD spectra of Y/1 catalyst in various solvents.
La
Pr
Sm
Gd
Er
Yb
Y
Y
Y
Y
Y
oselectivity among the RE examined (entry 2). The absolute
configuration of the major enantiomer was not uniform in
RE screening (entries 1-8), presumably because the struc-
tural flexibility of 1 would lead to the construction of RE/1
complexes with different structural motifs depending on
slight differences in the ionic radii of the REs.11 The highly
coordinative nature of 1 through metal coordination and
hydrogen bonding led us to investigate the solvent effect of
the reaction (entries 9-13), revealing that CH2Cl2 was a
suitable solvent in the present reaction to give the desired
product 4aa in 88% yield and 99% ee, likely due to the
enhanced hydrogen bonding control for Y/1 complexation
and/or the approaching direction of vinyl ketone 3 (entry
12). Indeed, CD spectra of the Y/1 solution in various
9
10
11
12
13
DMF
toluene
CH2Cl2
CH2Cl2
95
99
97
a 2a, 0.3 mmol; 3a, 0.2 mmol. b Determined by 1H NMR with Bn2O as
an internal standard. c Determined by HPLC analysis.
Initial attempts were devoted to identifying a suitable RE
in combination with the amide-based ligand 1 in the reaction
of 2-cyanocyclopentanone (2a) and naphthyl vinyl ketone
(3a).10 The catalyst was prepared by mixing RE(OiPr)3 and
1 in a 1:2 ratio, and the reactions were run with 10 mol %
of catalyst (based on RE) in AcOEt solvent at -20 °C. As
summarized in Table 1, Y(OiPr)3 afforded the best enanti-
(4) For selected examples of catalytic asymmetric conjugate addition
of R-substituted R-cyanocarbonyl pronucleophiles for the construction of
quaternary stereogenic centers, see: (a) Sawamura, M.; Hamashima, H.;
Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295. (b) Taylor, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2003, 125, 11204. (c) Taylor, M. S.; Zalatan,
D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127,
1313. (d) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127,
8948. (e) Takenaka, K.; Minakawa, M.; Uozumi, Y. J. Am. Chem. Soc.
2005, 127, 12273. (f) Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.; Li, B.-J.; Wu,
Y.; Ding, L.-S.; Chen, Y.-C. Chem.sEur. J. 2007, 13, 319. (g) Wang, B.;
Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768.
(h) Wang, X.; Kitamura, M.; Maruoka, K. J. Am. Chem. Soc. 2007, 129,
1038. (i) Bell, M.; Poulsen, T. B.; Jørgensen, K. A. J. Org. Chem. 2007,
72, 3053. (j) Marini, F.; Sternativo, S.; Del Verme, F.; Testaferri, L.; Tiecco,
M. AdV. Synth. Catal. 2009, 351, 1801. (k) Li, H.; Song, J.; Deng, L.
Tetrahedron 2009, 65, 3139. For a review, see: (l) Jautze, S.; Peters, R.
Synthesis 2010, 365.
(2) For general reviews for catalytic asymmetric conjugate addition, see:
(a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (b) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033. (c) Kanai, M.; Shibasaki, M. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York,
2000; p 569. (d) Yamaguchi, M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg,
Germany, 2003; Suppl. 1, p 151. (e) Alexakis, A.; Benhaim, C. Eur. J.
Org. Chem. 2002, 3221. (f) Christoffers, J.; Baro, A. Angew. Chem., Int.
Ed. 2003, 42, 1688. (g) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(3) For selected examples of catalytic asymmetric conjugate addition
of R-substituted ꢀ-ketoesters for the construction of quaternary stereogenic
centers, see: (a) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 16, 4057.
(b) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240. (c) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006,
45, 947. (d) Rigby, C. L.; Dixon, D. J. Chem. Commun. 2008, 3798. (e)
Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.; Maruoka,
K. Angew. Chem., Int. Ed. 2003, 42, 3796. (f) Ogawa, C.; Kizu, K.; Shimizu,
H.; Takeuchi, M.; Kobayashi, S. Chem. Asian J. 2006, 1-2, 121. (g)
Alema´n, J.; Reyes, E.; Richter, B.; Overgaard, J.; Jørgensen, K. A. Chem.
Commun. 2007, 3921. (h) Capuzzi, M.; Perdicchia, D.; Jørgensen, K. A.
Chem.sEur. J. 2008, 14, 128. (i) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu,
X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44,
105. (j) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli, M.;
Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem., Int. Ed.
2006, 45, 4966.
(5) For reviews on R-cyanocarboanions, see: (a) Arseniyadis, S.; Kyler,
K. S.; Watt, D. S. Org. React. 1984, 31, 1. (b) Fleming, F. F.; Shook, B. C.
Tetrahedron 2002, 58, 1. (c) Fleming, F. F.; Iyer, P. S. Synthesis 2006,
893.
(6) (a) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008,
130, 5630. (b) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 3779.
(7) (a) Nishida, A.; Yamanaka, M.; Nakagawa, M. Tetrahedron Lett.
1999, 40, 1555. (b) Stodulski, M.; Jazwinski, J.; Mlynarski, J. Eur. J. Org.
Chem. 2008, 5553. (c) Sudo, Y.; Shirasaki, D.; Harada, S.; Nishida, A.
J. Am. Chem. Soc. 2008, 130, 12588.
(8) For the utility of RE/1 catalysts and their related catalysts, see: (a)
Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2008, 49, 272.
(b) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 13860. (c) Mashiko, T.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 14990.
Org. Lett., Vol. 12, No. 7, 2010
1485

Table 2. Catalytic Asymmetric Conjugate Addition of R-Cyanoketones 2 and Vinyl Ketones 3 Promoted by a Y/1 Catalysta
d
a 2, 0.45 mmol; 3, 0.3 mmol. b Isolated yield. c With 1.1 g of 3c used. Yield was determined by H NMR analysis with Bn2O as an internal standard.
1
e 2a, 0.3 mmol; 3i, 0.45 mmol.
1486
Org. Lett., Vol. 12, No. 7, 2010

solvents showed different patterns, suggesting that chirop-
tically different complexes would be formed depending on
the properties of the solvent (Figure 1). The reaction with
the catalyst prepared from different ligand/metal ratios
indicated that ligand Y/1 ) 1:2 gave the best results.12
Catalyst loading can be reduced to 5 mol % to complete the
reaction with marginal loss of enantioselectivity (entry 13).
Having developed a suitable catalytic system for the
asymmetric conjugate addition of R-cyanoketone and vinyl
ketone, we then examined the substrate scope of the catalytic
asymmetric conjugate addition (Table 2).13,14 Whereas a loss
in enantioselectivity was detected in the reaction with a vinyl
ketone bearing no substituents on the aromatic ring (3b)
(entry 2), vinyl ketones with substituents at the meta or para
position of the aromatic ring provided the corresponding
products with high enantioselectivity regardless of their
electronic nature (entries 3-12). The reaction can be run on
a gram scale without any problem (entry 4). Vinyl ketones
bearing a coordinative benzoxazole group or a thiophen were
also applicable, albeit with lower enantioselectivity (entries
13 and 14). A significant decrease in enantioselectivity was
observed with vinyl ketone 3n, likely because the preferred
flat conformation of vinyl ketones is privileged in the
asymmetric environment of the catalyst (entry 15).15 The
reaction using 2-cyanocyclohexanone (2b) or 2-cyanocyclo-
heptanone (2c) proceeded sluggishly to give the correspond-
ing products (entries 16 and 17). Phenyl-fused cyanoketones
2d and 2e afforded lower enantioselectivity in the present
catalytic system (entries 18 and 19).
The conjugate addition product bearing a quaternary
stereogenic center and suitably installed functional groups
was converted to enantioenriched bicyclic compounds by
intramolecular cyclization (Scheme 2). Pinacol coupling of
4ac mediated by SmI2 exclusively afforded a diol with
bicyclo[3.3.0]octane core 5ac in 94% yield.16,17 Treatment
of 4ac with Raney nickel in glacial acetic acid under 4 atm
H2 atmosphere gave spiro-piperidine 6ac in 72% yield.4f,18
Scheme 2. Transformation of the Conjugate Addition Products
In summary, we documented a catalytic asymmetric
conjugate addition of R-cyanoketones 2 and vinyl ketones 3
with RE/amide-based ligand 1 catalytic system, affording
1,5-dicarbonyl compounds bearing a quaternary stereogenic
center. The product was transformed into enantioenriched
bicyclic compounds bearing functional groups.
(9) For selected examples of small peptide-based asymmetric catalysis,
see: (a) Oku, J.; Inoue, S. Makromol. Chem. 1979, 180, 1089. (b) Julia´, S.;
Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl. 1980, 19, 929. (c)
Colonna, S.; Molinari, H.; Banfi, S.; Julia´, S.; Masana, J.; Alvarez, A.
Tetrahedron 1983, 39, 1635. (d) Itsuno, S.; Sakakura, M.; Ito, K. J. Org.
Chem. 1990, 55, 6047. (e) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.;
Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910. (f) Zhao, Y.; Rodrigo, J.;
Hoveyda, A. H.; Snapper, M. C. Nature 2006, 443, 67. (g) Lewis, C. A.;
Chiu, A.; Kubryk, M.; Balsells, J.; Pollard, D.; Esser, C. K.; Murry, J.;
Reamer, R. A.; Hansen, K. B.; Miller, S. J. J. Am. Chem. Soc. 2006, 128,
16454. For reviews, see: (h) Hoveyda, A. H.; Hird, A. W.; Kacprzynski,
M. A. Chem. Commun. 2004, 1779. (i) Blank, J. T.; Miller, S. J. Biopolymers
(Pept. Sci.) 2006, 84, 38. (j) Kelly, D. R.; Roberts, S. M. Biopolymers (Pept.
Sci.) 2006, 84, 74. (k) Colby Davie, E. A.; Mennen, S. M.; Xu, Y.; Miller,
Acknowledgment. Financial support was provided by a
Grant-in-Aid for Scientific Research (S) from JSPS. Dr. M.
Shiro at Rigaku Coorporation is gratefully acknowledged for
the X-ray chrystallographic analysis of compound 4aa and
p-bromobenzoate of 6ac. We thank Prof. T. Ohwada and
Dr. Y. Otani at the University of Tokyo for technical
assistance with CD measurement.
S. J. Chem. ReV. 2007, 107, 5759, and references cited therein
.
(10) Ligand 1 was prepared from L-Val following the procedure
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
described in the literature. Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara,
Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342
.
(11) More clear tendency between ionic radii of REs and stereoselectivity
is observed for more structurally rigid catalysts: (a) Sasai, H.; Suzuki, T.;
Itoh, N.; Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 2567. (b)
Kobayashi, S.; Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett. 2001, 3,
165. (c) Hamada, T.; Manabe, K.; Ishikawa, S.; Nagayama, S.; Shiro, M.;
OL100183S
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 2989
.
(16) (a) Namy, J. L.; Girard, P.; Kagan, H. B. New J. Chem. 1977, 1,
5. (b) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693. For general reviews, see: (c) Edmonds, D. J.; Johnston, D.; Procter,
D. J. Chem. ReV. 2004, 104, 3371. (d) Dahle´n, A.; Hilmersson, G. Eur.
J. Inorg. Chem. 2004, 3393. (e) Gopalaiah, K.; Kagan, H. B. New J. Chem.
(12) The catalyst prepared in a ratio of Y(OiPr)3/1 ) 1:1 gave the product
in 91% yield and 24% ee under otherwise identical conditions.
(13) The absolute configuration of 4aa and 4ac was determined by X-ray
crystallographic analysis. See Supporting Information for details.
(14) The reaction using an acyclic R-cyanoketone or a ꢀ-substituted
enone gave no desired products. Experimental details are summarized in
Supporting Information.
2008, 32, 607
.
(17) Relative configuration was determined after converting to the
corresponding cyclic carbonate. See Supporting Information for details.
(18) Relative configuration was determined by X-ray crystallographic
analysis of the corresponding p-bromobenzoate. See Supporting Information
for details.
(15) The reaction with enone 3n using another RE/1 catalyst did not
improve the enantioselectivity. The results are summarized in Supporting
Information.
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