enantioselection, but marginally superior results were ob-
tained using (S)-SEGPHOS (L1) (entry 1).
Next, the scope of this process was explored (Table 2),
and a number of aromatic-tethered bis-R,ꢀ-unsaturated
Table 1. Survey of Chiral Ligands for Reductive Michael
Cyclization of 1aa
Table 2. Scope of Enantioselective Copper-Catalyzed Reductive
Michael Cyclizations
entry
ligand
drb
ee (%)c
1
2
3
L1
L2
L3
L4
L5
L6
10:1
9:1
6:1
6:1
5:1
6:1
94(+)
84(+)
81(-)
87(-)
84(-)
92(-)
4
5d
6
a Reactions were conducted using 0.065 mmol of 1a in THF (0.2 mL).
Unless otherwise stated, complete consumption of 1a was observed.
b Determined by 1H NMR analysis of the unpurified reaction mixtures.
c Determined by chiral HPLC analysis of the unpurified reaction mixtures.
The absolute stereochemistry of 2a was not determined. The sign of optical
rotation is provided in parentheses. d Reaction proceeded to 80% conversion
1
as determined by H NMR analysis.
a Isolated yields of pure major diastereomers unless otherwise specified.
b Determined by 1H NMR analysis of the unpurified reaction mixtures.
c Enantiomeric excess of major diastereomer as determined by chiral HPLC
analysis. The absolute stereochemistry was not determined. The sign of
optical rotation is provided in parentheses. d Yield of a mixture of inseparable
diastereomers. e Reaction conducted using (R)-BINAP (L4). f Reaction
conducted using (S)-DM-SEGPHOS (L2).
% of ligand, and 1.0 equiv of TMDS in THF at room
temperature, cyclization to the indane derivative 2a was
successful in all cases, and except when (R)-HEXAPHEMP
(L5) was employed (entry 5), complete consumption of
starting material was observed.10 Bisphosphines L1-L6
generally provided comparable levels of diastereo- and
(5) For stoichiometric reductive Michael cyclizations using Stryker’s
reagent, see: Kamenecka, T. M.; Overman, L. E.; Ly Sakata, S. K. Org.
Lett. 2002, 4, 79–82.
carbonyl compounds were found to undergo cyclization with
modest yields,11 but with reasonable to high diastereoselec-
tivities12 and high enantioselectivites. Using (S)-SEGPHOS
(6) For catalytic enantioselective reductive aldol reactions with alde-
hydes, see: (a) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem.
Soc. 2000, 122, 4528–4529. (b) Zhao, C.-X.; Duffey, M. O.; Taylor, S. O.;
Morken, J. P. Org. Lett. 2001, 3, 1829–1831. (c) Russell, A. E.; Fuller,
N. O.; Taylor, S. J.; Aurriset, S.; Morken, J. P. Org. Lett. 2004, 6, 2309–
2312. (d) Fuller, N. O.; Morken, J. P. Synlett 2005, 1459–1461. (e)
Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am. Chem. Soc.
2005, 127, 6972–6973. (f) Shiomi, T.; Ito, J.-i.; Yamamoto, Y.; Nishiyama,
H. Eur. J. Org. Chem. 2006, 5994–5600. (g) Chuzel, O.; Deschamp, J.;
Chausteur, C.; Riant, O. Org. Lett. 2006, 8, 5943–5946. (h) Bee, C.; Han,
A.; Hassan, S. B.; Iida, H.; Krische, M. J. J. Am. Chem. Soc. 2008, 130,
2746–2747. (i) Shiomi, T.; Adachi, T.; Ito, J.; Nishiyama, H. Org. Lett.
2009, 11, 1011–1014. For catalytic enantioselective reductive aldol reactions
with ketones, see: (j) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225–
4228. (k) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew.
Chem., Int. Ed. 2006, 45, 1292–1297. (l) Zhao, D.; Oisaki, K.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403–1407. (m) Zhao, D.; Oisaki,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440–14441.
(n) Shiomi, T.; Nishiyama, H. Org. Lett. 2007, 9, 1651–1654. (o) Lipshutz,
B. H.; Amorelli, B.; Unger, J. B. J. Am. Chem. Soc. 2008, 130, 14378–
14379. (p) Deschamp, J.; Riant, O. Org. Lett. 2009, 11, 1217–1220.
(7) A sequential organocatalytic asymmetric conjugate reduction-Man-
nich reaction of ꢀ,ꢀ′-disubstituted R,ꢀ-unsaturated aldehydes has been
reported: Zhao, G.-L.; Co´rdova, A. Tetrahedron Lett. 2006, 47, 7417–7421.
(8) Organocatalytic asymmetric reductive Michael cyclizations: (a)
Wang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005,
127, 15036–15037. (b) Michrowska, A.; List, B. Nature Chem. 2009, 1,
225–228. For related N-heterocyclic carbene-catalyzed Michael cyclizations,
see: (c) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 3107–3110. (d) Li, Y.; Wang, X.-Q.; Zheng, C.;
You, S.-L. Chem. Commun. 2009; DOI: 10.1039/b914805a.
(9) For reviews of copper hydride-catalyzed reactions, see: (a) Deutsch,
C.; Krause, N.; Lipshutz, B. H. Chem. ReV. 2008, 108, 2916–2926. (b)
Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed. 2007, 46, 498–504. (c)
Lipshutz, B. H. In Modern Organocopper Chemistry; Krause, N., Ed.;
Wiley-VCH: Weinheim, 2002; pp 167-187.
(10) No discernible differences in reaction efficiency were observed
between ligands L1-L4 and L6, which provided comparable conversions
(ca. g 85%) into indane 2a.
Org. Lett., Vol. 11, No. 20, 2009
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