to the substrate can result in substantial spectral
changes that affect the ability to selectively photo-
excite the catalyst-bound substrate (15). In con-
trast, the results summarized in Fig. 3 demonstrate
that our dual-catalytic system tolerates wide-ranging
structural variation (27). Successful substrates in-
clude aryl enones bearing electron-donating and
-withdrawing substituents, heteroaryl enones, and
g-substituted enones. The enantioselectivity re-
mains high for all of these cycloadducts regard-
less of the ultraviolet (UV) absorptivity of the
substrates (28). For example, the phenyl and
naphthyl enones leading to cyclobutanes 2a and
2g both provide high ee even though the UV
absorption of the latter extends to considerably
longer wavelengths (fig. S1). Consistent with our
studies of racemic crossed enone cycloadditions
(20), we observe the formation of readily separa-
ble by-products arising from competitive reduc-
tive coupling and aryl enone homodimerization
processes. The use of a fivefold excess of the
aliphatic enone increases the overall rate of for-
mation of [2 + 2] cycloadducts and minimizes the
formation of homocoupling products. Overall,
these results represent a substantial improvement
in the structural variety of enantioenriched [2 + 2]
cycloadducts available by catalysis. Each of the
previous reports of asymmetric catalytic photo-
cycloadditions has involved intramolecular reac-
tions of cyclic enone substrates and thus furnished
bicyclic products. Our intermolecular cycloaddi-
tion of acyclic enones can produce a diverse range
of simple monocyclic cyclobutane products in
One important advantage of this dual-catalytic
system is the functional independence of the
photocatalyst and the chiral Lewis acid catalyst
(29). Extensive variations can be made to the
structure of the chiral Lewis acid without any
deleterious effect on the photochemical properties of the Ru(bpy)32+ chromophore. This feature
facilitates both the optimization of the enantioselectivity and the discovery of complementary reactivity. For example, reduction of Schiff base
ligand 8 with NaBH4 afforded secondary amine
ligand 9, the Eu(OTf)3 complex of which was
also a highly enantioselective Lewis acid cocatalyst for [2 + 2] cycloaddition. These conditions,
however, favored the formation of 1,2-cis diastereo-mer 3 in good ee (Fig. 4A) (30). The scope of the
cycloaddition using 9 exhibits the same general
breadth as reactions conducted with ligand 8
(Fig. 4B), but with complementary diastereose-lectivity (31).
These studies demonstrate that transition-metal
photocatalysts are compatible with a variety of
structurally diverse chiral Lewis acid catalysts.
The factors governing the success of chiral Lewis
acids in asymmetric catalysis have been studied
for decades and are now well-understood (32).
The ability to combine the power and versatility
of chiral Lewis acids with the unique reactivity of
photocatalytically generated intermediates has the
potential to be a valuable platform for the devel-
opment of a wide range of broadly useful stereo-
References and Notes
1. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Comprehensive
Asymmetric Catalysis (Springer, Berlin, New York, 1999).
2. I. Ojima, Catalytic Asymmetric Synthesis (Wiley, Hoboken,
NJ, ed. 3, 2010).
3. J. Iriondo-Alberdi, M. F. Greaney, Eur. J. Org. Chem.
2007, 4801–4815 (2007).
4. N. Hoffmann, Chem. Rev. 108, 1052–1103 (2008).
5. H. Rau, Chem. Rev. 83, 535–547 (1983).
6. Y. Inoue, Chem. Rev. 92, 741–770 (1992).
7. J. A. Le Bel, Bull. Soc. Chim. Fr. 22, 337 (1874).
8. W. Kuhn, E. Knopf, Naturwissenschaften 18, 183
9. M. Demuth et al., Angew. Chem. Int. Ed. Engl. 25,
10. L. M. Tolbert, M. B. Ali, J. Am. Chem. Soc. 104, 1742–1744
11. T. Bach, H. Bergmann, K. Harms, Angew. Chem. Int. Ed.
39, 2302–2304 (2000).
12. F. Toda, H. Miyamoto, S. Kikuchi, J. Chem. Soc.
Chem. Commun., 621–622 (1995).
Fig. 4. Diastereocontrol through independent
modification of chiral Lewis acid structure. (A)
Stereoselective access to 1,2-cis cycloadducts 3
through reduction of chiral Schiff base ligand 8 to
amine 9. (B) Substrate scope of 1,2-cis cyclobutanes
via enantioselective [2 + 2] photocycloaddition. Dias-tereomer ratios measured by 1H-NMR analysis of the
unpurified reaction mixtures. Reported yields represent total isolated yields of the 1,2-cis and 1,2-trans
isomers. For each entry, yields represent the average of two reproducible experiments. *Reaction
conducted for 14 hours. †Reaction conducted for
36 hours. ‡Reaction conducted at 37°C. §Isolated
yield of only cis isomer.
3a: 78% yield
3d: 74% yield†
3b: 79% yield
3h: 70% yield
3k: 80% yield*, ‡
3j: 67% yield†
3l: 72% yield †
3g: 64% yield
3c: 65% yield
3e: 80% yield*
3n: 80% yield
3m: 49% yield †, §
5 mol% Ru(bpy)3Cl2
10 mol% Eu(OTf)3
30 mol% 8 or 9
5 equiv. 1
7:1 dr ( 2:3)
4.5:1 dr (3:2)
visible light, rt, 14 h