C O M M U N I C A T I O N S
Table 1. Preliminary Scope of the Catalytic Asymmetric
R-Allylation of Aldehydes
and HPLC departments for performing analyses and Simone Marcus
for technical support.
Supporting Information Available: Experimental procedures,
compound characterization, NMR-spectra, and HPLC and GC traces.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566-1568. (b) Uraguchi, D.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 5356-5357. For reviews see: (c) Akiyama, T.; Itoh, J.;
Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999-1010. (d) Connon, S. J.
Angew. Chem., Int. Ed. 2006, 45, 3909-3912 and references therein.
(2) List, B. Chem. Commun. 2006, 819-824 and references therein.
(3) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193-4195.
(4) For earlier attempts, see: Lacour, J.; Hebbe-Viton, V. Chem. Soc. ReV.
2003, 32, 373-382.
(5) (a) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368-13369.
(b) Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498-7499.
(6) For reviews see: (a) Trost, B. M.; Vranken, D. L. V. Chem. ReV. 1996,
96, 395-422. (b) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1-14. (c)
Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921-2943.
(7) Chiral phosphates have been used before in the Pd-catalyzed asymmetric
hydrocarboxylation of olefins. See: Alper, H.; Hamel, N. J. Am. Chem.
Soc. 1990, 112, 2803-2804.
(8) For the application of chiral phosphoric acids in metal mediated asym-
metric transformations see: (a) Lacasse, M.-C.; Poulard, C.; Charette, A.
B. J. Am. Chem. Soc. 2005, 127, 12440-12441. (b) Komanduri, V.;
Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448-16449. Also see:
(c) Llewellyn, D. B.; Adamson, D.; Arndtsen, B. A. Org. Lett. 2000, 2,
4165-4168.
(9) For reviews see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363-5367. (b) Christoffers, J.; Baro, A. AdV.
Synth. Catal. 2005, 347, 1473-1482. (c) Trost, B. M.; Jiang, C. Synthesis
2006, 369-396.
(10) For a direct intramolecular R-alkylation of aldehydes see: (a) Vignola,
N.; List, B. J. Am. Chem. Soc. 2004, 126, 450-451. For tin enolate-
based approaches see: (b) Doyle, A. G.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2007, 46, 3701-3705 and the references therein.
(11) For the R-allylation using phase transfer catalysts see: Ooi, T.; Maruoka,
K. Angew. Chem., Int. Ed. 2007, 46, 4222-4266 and references therein.
For a nonasymmetric direct R-allylation of aldehydes see: Kimura, M.;
Horino, Y.; Mukai, R.; Tanaka, S.; Tamaru, Y. J. Am. Chem. Soc. 2001,
123, 10401-10402.
(12) For reviews about allylic alkylation of ketone enolates see: (a) Tunge, J.
A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715-1726. (b) Braun, M.;
Meier, T. Angew. Chem., Int. Ed. 2006, 45, 6952-6955. (c) Braun, M.;
Meier, T. Synlett 2006, 661-676. For recent advances see: (d) Benenna,
D. C.; Stolz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045. (e) Trost,
B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846-2847. (f) Graening,
T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 17192-17193. (g)
Belanger, E.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am.
Chem. Soc. 2007, 129, 1034-1035.
entry
R1
R2
R3
yield (%)
era
1
2
3
4
5b
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
2a
2b
2c
2d
2e
2f
85
89
84
85
74
76
71
80
98.5:1.5
97:3
98:2
98:2
97:3
97.5:2.5
97:3
93:7
4-Me-C6H4
3-Me-C6H4
3-F-C6H4
2-F-C6H4
4-i-Bu-C6H4
2-naph
H
H
H
H
H
H
H
2g
2h
2-thiophenyl
9
H
2i
45
95:5
10c
Me
Me
Me
c-hex
Ph
H
Me
Ph
2j
2k
2l
65
40
82
85:15
96:4
91:9
11d,e
12d,e
Ph
a From GC or HPLC. b Reaction run at 50 °C. c Reaction run at 110 °C
in toluene. d Reaction run at 60 °C. Reaction run for 72 h.
e
good yields (71-89%) and enantiomeric ratios (93:7 to >98:2)
(entries 1-8).18 The allylated product of 2,3-dihydro-1-indanone
derived aldehyde (2i) was obtained in high er but in moderate yield
(entry 9). 2-Alkylpropionaldehydes can also be used but rather harsh
reaction conditions are necessary, and the enantioselectivity obtained
so far is only moderate (entry 10). Substitution at the 3-position of
the allyl group has also been investigated; 3-methyl and 3-phenyl
substituted products were obtained in 96:4 and 91:9 er respectively
(entries 11, 12).
A short application of our method in a formal synthesis of
(+)-cuparene has also been developed. Rh-catalyzed hydroacylation
of aldehyde 2b gave cuparenone, which can be converted into
cuparene via Reetz dimethylation (eq 3).19
(13) For a catalytic enantioselective allylic alkylation of enamines, see: (a)
Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7720-7721.
For auxiliary-based approaches see: (b) Hiroi, K.; Abe, J.; Suya, K.; Sato,
S. Tetrahedron Lett. 1989, 30, 1543-1546. (c) Hiroi, K.; Abe, J.
Tetrahedron Lett. 1990, 31, 3623-3626. (d) Hiroi, K.; Koyama, T.; Anzai,
K. Chem. Lett. 1990, 235-238. (e) Hiroi, K.; Abe, J.; Suya, K.; Sato, S.;
Koyama, T. J. Org. Chem. 1994, 59, 203-213.
(14) Ibrahem, I.; Co´rdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952-1956.
(15) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D.
W. C. Science 2007, 316, 582-585.
In conclusion, we have developed a highly enantioselective
R-allylation of R-branched aldehydes that creates all-carbon
quaternary stereogenic centers. This reaction represents the first
example of a catalytic enantioselective R-allylation of R-branched
aldehydes. The phosphoric acid cocatalyst (TRIP) plays a dual
catalytic role: as Brønsted acid it acts as the proton source while
the resulting conjugate base functions as the counteranion/ligand
for the cationic π-allyl-Pd-intermediate. To our knowledge, this is
the first time that a chiral anionic ligand is applied for achieving
asymmetric induction in a palladium-catalyzed allylic alkylation
reaction. We are aware of the implications of our results for other
transition metal-catalyzed reactions and continue to explore ACDC
as a powerful new strategy for asymmetric catalysis.
(16) (a) Murahashi, S.-I.; Makabe, Y. Tetrahedron Lett. 1985, 26, 5563-5566.
(b) Murahashi, S.-I.; Makabe, Y.; Kunita, K. J. Org. Chem. 1988, 53,
4489-4495.
(17) For example, if aldehyde 1a, N-benzyl allyl amine, Pd(PPh3) (3 mol %),
and (R)-TRIP (1.5 mol %) were reacted at 40 °C, full conversion to
R-allylated aldehyde 2a in 89:11 er was obtained.
(18) The initial reaction product is the corresponding imine as confirmed by
GC-MS. Consequently, if the reaction of aldehyde 1a is worked up with
NaBH4 rather than by acidic hydrolysis, the corresponding amine is
obtained:
Acknowledgment. We thank Sebastian Hoffmann, Marcello
Nicoletti, and Xiaoguang Li for kindly donating some racemic
aldehydes. Generous support by the MPG, Novartis, the DFG, and
by the FCI is gratefully acknowledged. We wish to thank our GC
(19) Reetz, M. T.; Westermann, J.; Kyung, S.-H. Chem. Ber. 1985, 118,
1050-1057.
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