REPORTS 18. D. K. Bediako et al., J. Am. Chem. Soc. 134, 6801–6809 (2012). 19. R. D. L. Smith et al., Science 340, 60–63 (2013). 20. D. A. Corrigan, R. M. Bendert, J. Electrochem. Soc. 136, 723–728 (1989). 21. M. Gong et al., J. Am. Chem. Soc. 135, 8452–8455 (2013). 22. R. L. LeRoy, Int. J. Hydrogen Energy 8, 401–417 (1983). 23. B. MacDougall, D. F. Mitchell, M. J. Graham, J. Electrochem. Soc. 127, 1248–1252 (1980). 24. D. A. Corrigan, S. L. Knight, J. Electrochem. Soc. 136, 613–619 (1989).

25. D. Tuomi, J. Electrochem. Soc. 112, 1–12 (1965). 26. P. Oliva et al., J. Power Sources 8, 229–255 (1982). 27. S. K. Behura, P. Mahala, A. Ray, J. Electron Devices 10, 471–482 (2011). 28. D. V. Esposito, I. Levin, T. P. Moffat, A. A. Talin, Nat. Mater. 12, 562–568 (2013). 29. X. Wu, E. S. Yang, IEEE Electron Device Lett. 11, 315–317 (1990).

Supplementary Materials

Acknowledgments: Supported by a Stinehart/Reed Award from the Stanford Precourt Institute for Energy, a Stanford

3 June 2013; accepted 7 October 2013 10.1126/science.1241327

GCEP grant, and an NSF Graduate Fellowship (M.J.K.). We thank C. Chidsey for helpful discussions.

www.sciencemag.org/content/342/6160/836/suppl/DC1 Materials and Methods Figs. S1 to S13 Tables S1 to S6

R. Brimioulle and T. Bach* Asymmetric catalysis of photochemical cycloadditions has been limited by the challenge of suppressing the unselective background reaction. Here, we report that the high cross-section pp* transition of 5,6-dihydro-4-pyridones, a versatile class of enone substrates, undergoes a >50 nanometer (nm) bathochromic absorption shift upon Lewis acid coordination. Based on this observation, enantioselective intramolecular [2+2] photocycloaddition reactions (82 to 90% enantiomeric excess) were achieved with these substrates using 0.5 equivalents of a chiral Lewis acid upon irradiation at a wavelength of 366 nm. One of the products was applied as a key intermediate in the total synthesis of (+)-lupinine and the formal synthesis of (+)-thermopsine. Several enones show similar bathochromic shifts in the presence of a Lewis acid, indicating that chiral Lewis acid catalysis may be a general approach toward enantioselective enone [2+2] photocycloadditions.

T

of axially chiral coumarins (11), the sensitized intramolecular [2+2] PCA of N-unsubstituted quinolones (12), or the Lewis acid–catalyzed intramolecular [2+2] PCA of 4-substituted cou-

absorption

he [2+2] photocycloaddition (PCA) of enones was discovered in 1908 by Ciamician and Silber (1), early pioneers (2) of organic photochemistry. Over the years this reaction has become one of the most widely applied photochemical transformations (3–7). The reaction occurs on the triplet manifold and can be initiated by direct excitation or sensitization (8). The key intermediate is the lowest-lying triplet (T1) state of the enone, which has pp* character and to which another olefin can add, leading via a 1,4-diradical to four-membered cyclobutane rings. With the advent of enantioselective synthesis and with increasing attention given to enantiomerically pure products (9), attempts were undertaken to render the enone [2+2] PCA enantioselective. Although a chiral auxiliary-based approach—first demonstrated by Tolbert and Ali (10)—is viable, it lacks brevity (two steps are required to attach and remove the auxiliary) and general applicability (many enones are cyclic compounds without a possible site for auxiliary attachment). Nonauxiliary-based approaches have been restricted to aromatic a,b-unsaturated lactones and lactams with a narrow substitution pattern and with very limited use in natural product synthesis. Examples include the intermolecular [2+2] PCA

wavelength [nm] 1

O

*Corresponding author. E-mail: [email protected]

840

O

hν (λ = 366 nm) 3 (50 mol%) −70 °C (CH2Cl2)

N

N 84%

O 1

Lehrstuhl für Organische Chemie I and Catalysis Research Center, Technische Universität München, D-85747 Garching, Germany.

1·EtAlCl2

1·BCl3

H

H

N

H

O

Br3Al

B

O CF3 3

2 (88% ee)

Fig. 1. Ultraviolet-visible spectra of substrate 1 in the presence of the Lewis acids and formation of compound 2 in an enantioselective [2+2] PCA reaction using chiral Lewis acid 3. Et, ethyl; h, Planck’s constant; n, frequency.

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marins (13, 14). Unlike for typical enones, the Τ1 state of the latter substrates cannot be accessed upon direct excitation because internal conversion from the first excited singlet state (S1) to the ground state (S0) is rapid (15). Intramolecular [2+2] PCA proceeds on the singlet hypersurface with medium efficiency at wavelength l = 300 nm (14) and with low efficiency at l = 366 nm (13). The known fact (15–17) that Lewis acid coordination to coumarins enhances the lifetime of the S1 state and allows for the population of the T1 state via S1 was exploited to catalyze the [2+2] PCA at l = 366 nm. Fluorescence experiments confirmed an increased lifetime of the S1 state (14), and the catalyzed reaction was shown to occur on the triplet hypersurface (13). The present study was concerned with a synthetically useful class of enones, 5,6-dihydro-4pyridones, and their intramolecular [2+2] PCA reactions in the presence of a chiral Lewis acid. This reaction was first described in its intermolecular variant by Neier et al. (18–20). The intramolecular variant has been later applied to natural product synthesis, in particular by Comins et al. (21–23). The substrates attracted our interest because they exhibit an extensive bathochromic

Enantioselective Lewis Acid Catalysis of Intramolecular Enone [2+2] Photocycloaddition Reactions

REPORTS

O

N

O

H

H

N

Me

O

H

H

N

H

5 48% (82% ee)

4 81% (88% ee) O

H

H

O

O

O

H

O

H

6 87% (80% ee) O

H

H Cl

N

N

H

H

N

Me

H

O

O

7 84% (90% ee)

8 83% (81% ee)

Ph H

O

MeO CF3

N

9 83% (82% ee)

10 41% (81% ee)

Br3Al

F 3C HN

O

B

H 1

2 10a

N

O

H

O

O

O

H

H

O

10

N

Me

H

O 11

O

12⋅3

Fig. 2. Structures of compounds 4 to 10, which were formed in the enantioselective enone [2+2] PCA reaction using chiral Lewis acid 3. Compounds 5 and 10 were formed simultaneously from the same irradiation precursor in 89% combined yield. Mosher ester 11 was obtained starting from photoproduct 8 in two steps, confirming the absolute configuration of the enantiomers formed in the [2+2] PCA reaction (see supplementary materials). The configuration of compound 8 can be explained by the proposed conformation of the complex of 12 with Lewis acid 3. Me, methyl; Ph, phenyl. www.sciencemag.org

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described previously (14). The generality of the method was shown by employing several other acylated 5,6-dihydro-4-pyridones as substrates (Fig. 2); these compounds delivered products 4 to 9 in high yields (75 to 87%) and enantioselectivities (80 to 90% ee). The lower yield of product 5 is due to concomitant formation of by-product 10, which appears at first sight to be the product of a subsequent Norrish type II fragmentation. However, monitoring the reaction course indicated that the formation of product 10 occurs parallel to the formation of product 5 (see fig. S3). After reduction of product 8 to the respective alcohol, an acylation with (R)-(–)-a-methoxy-atrifluoromethylphenylacetyl chloride was possible, which delivered the (S)-configured ester 11 (Fig. 2). Analysis of this ester according to the Mosher method (25, 26) suggests the absolute configuration of the 10-methyl-6-oxodecahydro1-10-methanopyrido[1,2-a]azepine skeleton to be (1S, 2R, 10R, 10aS). This outcome is in agreement with a postulated coordination of the precursor of product 8, substrate 12, to the Lewis acid as depicted in Fig. 2 (27), and an intramolecular approach of the olefin to the double bond in a Si-face attack relative to the enone a-carbon atom. Applications to the synthesis of lupin alkaloids were pursued to further substantiate the configuration assignment and to show the synthetic utility of the enantioselective enone [2+2] PCA reaction. Many of these alkaloids exhibit a central quinolizidine skeleton, which is built up with high selectivity in the course of the photochemical reaction and which represents the core structure of compounds 2, 4, 5, 6, and 9. Cleavage of the cyclobutane ring between carbon atoms C8 and C8a in the hexahydro-1H,5H-cyclobuta[ij]quinolizine1,5-dione ring system would enable ready access to quinolizidines. Although this ring cleavage is already implemented in product 10, further functionalization appeared difficult. However, it was possible to displace the chlorine substituent of product 9 by various nucleophiles in an eliminationaddition reaction. For the synthesis of the prototypical quinolizidine alkaloid lupinine (28, 29), the introduction of an oxygen atom was required (Fig. 3). Employing para-methoxybenzyl alcohol (PMBOH) as nucleophile, product 13 was obtained in 59% yield as a single enantiomer after appropriate purification. Reductive ring opening of the C8-C8a bond was best achieved via the respective xanthate (30). Diastereoselective reduction of ketone 13 gave the secondary alcohol 14, which was converted into xanthate 15. Generation of the secondary radical with azobis(isobutyronitrile) (AIBN) as the initiator led to the desired fragmentation, and the primary PMBO-substituted radical was trapped with tributyltin hydride. Conversion of ring-opening product 16 to lupinine (18) was performed by lactam reduction to amine 17, followed by concomitant double bond hydrogenation and ether hydrogenolysis. The enantiomerically pure product turned out to be dextrorotatory (specific rotation

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was observed, which led to the formation of the desired [2+2] PCA product 2. The reaction was regio- and diastereoselective; that is, only a single product was obtained as a mixture of enantiomers. Different attempts to determine the enantiomeric purity of this product failed, and it was necessary to derivatize the product before measuring the enantiomeric excess (ee). The preferred derivatization method included diastereoselective reduction of the ketone to a secondary alcohol and subsequent benzoylation with 3,5-dinitrobenzoyl chloride (see fig. S2). Under optimized conditions, the PCA product 2 was obtained in 84% yield and with 88% ee. The success of the reaction depends on the concentration and the solvent purity. The optimum substrate concentration was found to be 20 mM. A decrease of the catalyst loading leads to a decrease in enantioselectivity [64% ee at 40 mole % (mol %); 50% ee at 30 mol %], which is likely related to the mode of action of the catalyst (see below). The solvent (CH2Cl2) had to be dried over 4 Å molecular sieves to a residual water content of 95% ee)

9 82% ee

H

B

8

O

O

OPMB

8a

A

H

RO

H

14: R = H 15: R = C(S)SMe

C 87%

H

H

N

E

OPMB

H

N

F

OPMB

O

N

OH

83%

76% 16

17

18

Fig. 3. Enantioselective total synthesis of (+)-lupinine starting from 9. (A) (i) para-Methoxybenzyl alcohol, i-Pr2NEt, room temperature (r.t.), 20 hours; (ii) chiral high-performance liquid chromatography (HPLC) separation. i-Pr, isopropyl. (B) NaBH4, –78°C → r.t., 16 hours (solvent: MeOH). OPMB, paramethoxybenzyloxy. (C) (i) NaH, 0°C, 30 min [N,N-dimethylformamide (DMF)]; (ii) CS2, 0°C, 30 min, r.t., 2.5 hours (DMF); (iii) MeI, r.t., 3 hours (DMF). (D) HSnBu3, AIBN, 75°C, 4 hours (PhH). Bu, butyl. (E) LiAlH4, reflux, 3 hours (tetrahydrofuran). (F) H2, [Pd/C], r.t., 5 days, (MeOH/HOAc). OAc, acetate.

O

O

H Cl

N

H

N

H

H

O

N

O

N

99%

H

H

D O

86%

O

19

9

H

B

8

82%

O

N

8a

A

H

RO

H

20: R = H 21: R = C(S)SMe

C 90% O

H N

N

76%

O 22

H

O

H E

N

N

N

N

ref. (32)

O 23

O

24

Fig. 4. Enantioselective formal synthesis of (+)-thermopsine starting from 9. (A) 2-Pyridone, K2CO3, r.t., 16 hours (DMF). (B) NaBH4, –78°C → r.t., 16 hours (MeOH). (C) (i) NaH, 0°C, 30 min (DMF); (ii) CS2, 0°C, 30 min, r.t., 2.5 hours (DMF); (iii) MeI, r.t., 3 hours (DMF). (D) HSnBu3, AIBN, reflux, 3.5 hours (PhMe). (E) Raney-Ni, H2, 20 hours (EtOH).

842

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catalyzed enone [2+2] PCA to other substrates. It is evident that the mode of action in the case of enones is different from that in the specific case of coumarin [2+2] PCA. There is no increase in fluorescence due to Lewis acid coordination (see fig. S6), and the bathochromic shift induced by the Lewis acid is large (≥50 nm), as opposed to the minimal shift (≤10 nm) observed upon Lewis acid coordination to coumarins. Apart from the successful enantioface differentiation, the most relevant argument to explain the enantioselectivity is the fact that the strong absorption of the enone–Lewis acid complex prevents a reaction of uncomplexed enone and suppresses the racemic background reaction by avoiding an excitation of the np* band at l ≅ 360 nm. At lower catalyst loading, the concentration of uncomplexed enone increases, and the reaction is less enantioselective.

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1. G. Ciamician, P. Silber, Ber. Dtsch. Chem. Ges. 41, 1928–1935 (1908). 2. G. Ciamician, Science 36, 385–394 (1912). 3. M. T. Crimmins, T. L. Reinhold, Org. React. 44, 297–588 (1993). 4. J. P. Hehn, C. Müller, T. Bach, in Handbook of Synthetic Photochemistry, A. Albini, M. Fagnoni, Eds. (Wiley-VCH, Weinheim, Germany, 2009), pp. 171–215. 5. J. D. Winkler, C. M. Bowen, F. Liotta, Chem. Rev. 95, 2003–2020 (1995). 6. J. Iriondo-Alberdi, M. F. Greaney, Eur. J. Org. Chem. 2007, 4801–4815 (2007). 7. T. Bach, J. P. Hehn, Angew. Chem. Int. Ed. 50, 1000–1045 (2011). 8. D. I. Schuster, G. N. Lem, A. Kaprinidis, Chem. Rev. 93, 3–22 (1993). 9. W. A. Nugent, T. V. RajanBabu, M. J. Burk, Science 259, 479–483 (1993). 10. L. M. Tolbert, M. B. Ali, J. Am. Chem. Soc. 104, 1742–1744 (1982). 11. M. Sakamoto et al., J. Am. Chem. Soc. 130, 1132–1133 (2008). 12. C. Müller, A. Bauer, T. Bach, Angew. Chem. Int. Ed. 48, 6640–6642 (2009). 13. H. Guo, E. Herdtweck, T. Bach, Angew. Chem. Int. Ed. 49, 7782–7785 (2010). 14. R. Brimioulle, H. Guo, T. Bach, Chemistry 18, 7552–7560 (2012). 15. F. D. Lewis, S. V. Barancyk, J. Am. Chem. Soc. 111, 8653–8661 (1989). 16. F. D. Lewis, D. K. Howard, J. D. Oxman, J. Am. Chem. Soc. 105, 3344–3345 (1983). 17. H. Görner, T. Wolff, Photochem. Photobiol. 84, 1224–1230 (2008). 18. P. Guerry, R. Neier, Chimia (Aarau) 41, 341–342 (1987). 19. P. Guerry, R. Neier, J. Chem. Soc. Chem. Commun. 1989, 1727–1728 (1989). 20. P. Guerry, P. Blanco, H. Brodbeck, O. Pasteris, R. Neier, Helv. Chim. Acta 74, 163–178 (1991). 21. D. L. Comins, X. Zheng, J. Chem. Soc. Chem. Commun. 1994, 2681–2682 (1994). 22. D. L. Comins, Y.-M. Zhang, X. Zheng, Chem. Commun. 1998, 2509–2510 (1998). 23. D. L. Comins, X. Zheng, R. R. Goehring, Org. Lett. 4, 1611–1613 (2002). 24. D. I. Schuster, in The Photochemistry of Enones, Part 2, S. Patai, Z. Rappoport, Eds. (Wiley, Chicester, UK, 1989), pp. 623–756. 25. J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 95, 512–519 (1973). 26. T. R. Hoye, C. S. Jeffrey, F. Shao, Nat. Protoc. 2, 2451–2458 (2007).

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Cl

starting material. A selective reduction of the double bond in intermediate 22 was facilitated by hydrogen and Raney nickel–providing compound 23, which had been previously synthesized in racemic form by a different route and has been shown to be converted into racemic thermopsine in three steps (32). The synthesis of compound 23 thus constitutes a formal synthesis of (+)-thermopsine. Extensive mechanistic studies elucidating the effect of the Lewis acid on the reaction course have not yet been performed. However, we showed that many enones manifest a similarly strong absorption shift in the presence of Lewis acids (see figs. S4 and S5), which should open the possibility to extend the enantioselective Lewis acid–

REPORTS 27. E. Canales, E. J. Corey, J. Am. Chem. Soc. 129, 12686–12687 (2007). 28. P. Karrer, F. Canal, K. Zohner, R. Widmer, Helv. Chim. Acta 11, 1062–1084 (1928). 29. M. Hajri, C. Blondelle, A. Martinez, J.-L. Vasse, J. Szymoniak, Tetrahedron Lett. 54, 1029–1031 (2013). 30. G. Adamson, A. L. J. Beckwith, M. Kaufmann, A. C. Willis, J. Chem. Soc. Chem. Commun. 1995, 1783–1784 (1995).

31. D. J. Robins, D. S. Rycroft, Magn. Reson. Chem. 30, 1125–1127 (1992). 32. D. Gray, T. Gallagher, Angew. Chem. Int. Ed. 45, 2419–2423 (2006). Acknowledgments: This work was supported by the Deutsche Forschungsgemeinschaft (Graduiertenkolleg GRK 1626 Chemical Photocatalysis) and by the Fonds der Chemischen Industrie (scholarship to R.B.). We thank O. Ackermann for help in conducting HPLC analyses.

Abrupt Shifts in Horn of Africa Hydroclimate Since the Last Glacial Maximum Jessica E. Tierney1* and Peter B. deMenocal2

uring the Early Holocene epoch between roughly 11 to 5 thousand years ago (ka), the presently hyperarid Saharan desert was dotted with large and small lakes, savannah grasslands, and in some regions, humid tropical forests and shrubs (1, 2). This “African Humid Period” (AHP) was a unique hydrological regime and has been a focal point of African paleoclimate studies, both for its climatological implications (3, 4) and its influence on the emergence of pharaonic civilization along the Nile (5, 6). The fundamental cause of the AHP—dramatic increases in summer precipitation triggered by orbital forcing of African monsoonal climate and amplified by oceanic and terrestrial feedbacks—is well understood (7, 8). However, the abruptness with which the AHP began and, most particularly, ended is still debated. Dust proxy data from the west coast of Africa indicate a rapid, century-scale termination of the AHP near 5 ka (9). In contrast, isotopic proxies from central Africa (10, 11) and pollen and sedimentological data from a lake in the eastern Sahara (12, 13) suggest a more gradual reduction in rainfall during the mid-Holocene tracking the orbital decline in boreal summer insolation. The discrepancy remains unresolved. Previous studies have attributed the difference in climate response to differing proxy sensitivities; for example, dust may respond nonlinearly to a gradual drying of the Sahara (14), and conversely, pollen data may

D

1

Woods Hole Oceanographic Institution, 266 Woods Hole Road, Woods Hole, MA 02540, USA. 2Lamont Doherty Earth Observatory, Palisades, NY 10964, USA. *Corresponding author. E-mail: [email protected]

be smoothed because of mixed contributions from distal terrains (2). Alternatively, there may be regional heterogeneity in both the timing and duration of the AHP termination, reflecting the variable sensitivity of different regions to certain feedback mechanisms (in particular, vegetation feedbacks) (3, 4, 6, 15, 16). East Africa and the Arabian Peninsula also experienced humid conditions during the Early Holocene (17, 18). Speleothem d18O data from southern Oman (Qunf Cave) and dust strontium isotopes off of Somalia suggest a gradual attenuation of humid conditions during the Holocene, much like the eastern Saharan pollen data (19, 20). These observations have led to the suggestion that the eastern Sahara and northeast Africa experienced a gradual end to the AHP (3, 4, 12, 15, 21) and that abrupt responses were therefore limited to the western Sahara. We revisited the timing and abruptness of transitions into and out of the AHP in northeast Africa using a new record of hydroclimate from a key, yet previously understudied, region: the Horn of Africa. This record is derived from a marine core (P178-15P) located in the Gulf of Aden (Fig. 1). The Gulf of Aden receives substantial amounts of terrestrial material during the summer monsoon season, when prevailing southwesterly winds transport dust from the Horn (Fig. 1 and fig. S1). Therefore, the terrestrial components (including organic matter) in the sediments predominantly reflect conditions in the Horn and Afar regions (supplementary materials). Twenty radiocarbon dates constrain the chronology of P178-15P and indicate an average sedimentation

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www.sciencemag.org/content/342/6160/840/suppl/DC1 Supplementary Text Figs. S1 to S8 NMR Spectra HPLC Spectra References (33–42) 16 August 2013; accepted 16 October 2013 10.1126/science.1244809

rate of 32 cm per thousand years (supplementary materials). We used the hydrogen isotopic composition of leaf waxes (dDwax) as a proxy for aridity and, more generally speaking, hydroclimate, including precipitation/evaporation balance and changes in regional convection. dDwax has been widely used in African paleoclimate and is an effective indicator of changes in the isotopic composition of precipitation (dDP) and aridity, with enriched isotopic values corresponding to drier conditions and depleted values to wetter conditions (10, 22). More generally, tropical water isotopes are good tracers of large-scale changes in atmospheric circulation (18, 23) and therefore reflect regional, rather than local, shifts in the hydrological cycle. Because Congo basin moisture is effectively blocked by the Ethiopian highlands and the Horn of Africa receives the majority of its rainfall from the Indian Ocean (24), we interpret the dDwax values to primarily represent changes in western Indian Ocean hydroclimate. The dDwax record from the Gulf of Aden indicates that Horn of Africa hydroclimate has changed dramatically during the past 40,000 years (Fig. 2). After the arid conditions of the Last Glacial Maximum (LGM) (26 to 19 ka), the Horn region experienced a severe dry period coincident with the North Atlantic cooling event, Heinrich Event 1 (H1) (Fig. 2), which is consistent with previous proxy (25) and model (23) evidence

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The timing and abruptness of the initiation and termination of the Early Holocene African Humid Period are subjects of ongoing debate, with direct consequences for our understanding of abrupt climate change, paleoenvironments, and early human cultural development. Here, we provide proxy evidence from the Horn of Africa region that documents abrupt transitions into and out of the African Humid Period in northeast Africa. Similar and generally synchronous abrupt transitions at other East African sites suggest that rapid shifts in hydroclimate are a regionally coherent feature. Our analysis suggests that the termination of the African Humid Period in the Horn of Africa occurred within centuries, underscoring the nonlinearity of the region’s hydroclimate.

Supplementary Materials

Fig. 1. A map of East Africa. The map includes topography, wind climatology for June-July-August (JJA) (46), the location of the study site (Gulf of Aden P178-15P; 11° 57.3′ N, 44° 18' E, 869 m water depth), and other sites mentioned in the text.

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Enantioselective Lewis Acid Catalysis of Intramolecular Enone [2+2] Photocycloaddition Reactions R. Brimioulle and T. Bach

Science 342 (6160), 840-843. DOI: 10.1126/science.1244809

ARTICLE TOOLS

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SUPPLEMENTARY MATERIALS

http://science.sciencemag.org/content/suppl/2013/11/13/342.6160.840.DC1

REFERENCES

This article cites 40 articles, 2 of which you can access for free http://science.sciencemag.org/content/342/6160/840#BIBL

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[2+2] Asymmetrically Catalysts in thermal reactions operate by lowering energy barriers of bound substrates, and thereby increasing the proportion of reagents that can proceed to products at a given temperature. In photochemical reactions, light provides the energy to surmount the barrier. It is therefore challenging to alter selectivity through catalysis, because the catalyst may not be bound when a given reagent absorbs the light. Brimioulle and Bach (p. 840) surmounted this problem in the light-induced intramolecular [2+2] cycloaddition of enones by using a catalyst that shifted the absorption wavelength of the bound substrate. The light was thus predominantly absorbed by substrate-catalyst complexes, enabling asymmetric induction by the catalyst to provide enantiomerically enriched products.