Enantioselective Diels–Alder Reactions of Cyclohexa-1, 3-diene and

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Enantioselective Diels−Alder Reactions of Cyclohexa-1,3-diene and Chalcones Catalyzed by Intramolecular Silicon−Sulfur Lewis Pairs as Chiral Lewis Acids Polina Shaykhutdinova and Martin Oestreich* Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 115, 10623 Berlin, Germany S Supporting Information *

ABSTRACT: The stereoselective preparation of diastereomeric dihydrosilepine-derived silicon cations decorated with another binaphthyl unit at the silicon atom is described. A sulfide donor attached to that additional binaphthyl substituent forms an intramolecular Lewis pair with the electron-deficient silicon atom, as verified by 29Si NMR spectroscopy. Both chiral sulfurstabilized silicon cations act as catalysts in the difficult Diels−Alder reaction of cyclohexa-1,3-diene and chalcone derivatives. Both Lewis acids induce enantioselectivity, but the S,S relative configuration is superior to the S,R configuration. With the former diastereomer, enantiomeric excesses of close to 60% are obtained. These values are the highest achieved to date in this seemingly trivial cycloaddition.

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INTRODUCTION Diels−Alder cycloadditions of electronically unbiased cyclohexa-1,3-dienes and chalcones belong to those seemingly trivial transformations that are in reality highly challenging. Aside from examples promoted by either ultrahigh pressure1 or microwave irradiation,2 the reaction of parent cyclohexa-1,3diene (1) and chalcone (2) itself had been elusive prior to our recent work.3 We introduced ferrocene-4,5 as well as sulfurstabilized6 silicon cations as Lewis acids for catalyzing this and related Diels−Alder reactions of 1 at low temperatures. While enantioselective variants employing planar chiral, ferrocenebased catalysts had failed,7 we found axially chiral silicon cation (S)-4 intramolecularly stabilized by a sulfur donor to induce little but appreciable enantioselection (1/2 → 3, Scheme 1).8−10 That limited precedence stands in contrast to the success achieved with chiral silicon Lewis acids in Diels−Alder reactions of cyclopentadiene and cinnamates11−13 and selected α,β-unsaturated aldehydes.14 With catalyst (S)-4 as a promising starting point, we added another chiral element to the sulfur tether, resulting in catalyst (S,S)-5 (Scheme 1). We describe here the stereoselective synthesis and spectroscopic characterization of the diastereomeric silicon Lewis acids (S,S)-5 and (S,R)-5 (not shown). Their application to enantioselective Diels−Alder reactions of cyclohexa-1,3-diene (1) and various chalcones leads to greatly improved asymmetric induction.

Scheme 1. Challenging Diels−Alder Reaction of Cyclohexa1,3-diene (1) and Chiral Sulfur-Stabilized Silicon Cations as Catalysts

Scheme 2. Preparation of the S-/R-Configured and Racemic Sulfide-Containing Substituent

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RESULTS AND DISCUSSION Stereoselective Synthesis of the Silicon Cation Precursors. Catalysts 5 are composed of an axially chiral dihydrosilepine backbone8 and an axially chiral sulfidecontaining substituent at its silicon atom. We decided to © XXXX American Chemical Society

Received: July 7, 2016

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DOI: 10.1021/acs.organomet.6b00548 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Scheme 3. Stereoselective Preparation of the Dihydrosilepine-Based Hydrosilanes

prepare both enantiomers of that substituent to access (S,S)-5 and (S,R)-5 diastereoselectively. The enantiomeric building blocks (S)-7 and (R)-7 were made from literature-known diiodides (S)-6 and (R)-6 by monoselective iodine−lithium exchange followed by trapping with the disulfide reagent (Scheme 2). Likewise, racemic rac-9 was obtained from the dibromide rac-8 by the same procedure15 (Scheme 2). The synthesis of the dihydrosilepine unit (S)-10 was accomplished in improved yield from 2,2′-dimethyl-1,1′binaphthalene according to our previously reported procedure8 (27% instead of 19% over two steps, not shown). (S)-10 was then reacted with metalated rac-9 to afford the desired hydrosilanes (S,S)-11 and (S,R)-11 in good yield (Scheme 3, center). The diastereomeric ratio of 50:50 was verified by 1H NMR spectroscopy, showing that neither diastereomer is formed preferentially. Accordingly, the diastereomerically pure hydrosilanes (S,S)-11 and (S,R)-11 were prepared from (S)-7 and (R)-7, respectively, in acceptable yields (Scheme 3, left and right). Generation of Sulfur-Stabilized Silicon Cations. The silicon cations 5 were generated in 1,2-Cl2C6H4 from the corresponding hydrosilanes 11 following the established protocol 16 of hydride abstraction with trityl tetrakis(pentafluorophenyl)borate, [Ph3C]+[B(C6F5)4]−. The resulting silicon cations were subsequently characterized by multinuclear NMR measurements, and the 29Si NMR chemical shifts were derived from 29Si DEPT experiments or 1H,29Si HMQC NMR spectra (Figure 1). The silicon−sulfur interaction in 5 generates in principle another stereogenic element, but the new central chirality at the sulfur atom is usually not resolved due to the dynamic equilibrium of the diastereomeric Lewis adducts.6,8 The 29Si NMR spectrum of (S,S)-5 (from (S,S)-11) indeed showed one resonance signal at δ 39.9 ppm. Conversely, three dramatically different resonance signals at δ 32.8, 7.5, and −14.5 ppm were seen in the 29Si NMR spectrum of (S,R)-5 (from (S,R)-11), implying additional ways of how the electrondeficient silicon atom in (S,R)-5 seeks stabilization.17 However, the addition of an external Lewis base such as benzophenone to this cocktail of cations led to clean formation of just one Lewis pair, (S,R)-5·OCPh2, with a 29Si NMR chemical shift of δ 31.7 ppm. The same outcome was found when starting from

Figure 1. Sulfur-stabilized silicon cations and their 29Si NMR chemical shifts.

Table 1. Probing Match/Mismatch Combinations in the Model Diels−Alder Reactiona,b

entry

silicon cation

conv. (%)c

yield (%)d

ee (%)e

1 2 3

(S,S)-5 (S,R)-5 (S,S)-5/(S,R)-5

99 99 99

61 57 53

34 13 25

a

All reactions were performed according to General Procedure 5 (GP5) in the Supporting Information at a dienophile concentration of 0.5 M. bDiastereomeric (trans:cis) and endo:exo ratios determined by GLC analysis of the crude material prior to purification. cDetermined by GLC analysis using triphenylmethane as the internal standard. d Analytically pure cycloadduct after flash column chromatography on silica gel. eDetermined by HPLC analysis using a chiral stationary phase.

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DOI: 10.1021/acs.organomet.6b00548 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Table 2. Enantioselective Diels−Alder Reactions of Cyclohexa-1,3-diene (1) and Chalcones Catalyzed by (S,S)-5a,b

a

All reactions were performed according to General Procedure 5 (GP5) in the Supporting Information at a dienophile concentration of 0.5 M. Diastereomeric (trans:cis) and endo:exo ratios determined by GLC analysis of the crude material prior to purification. cDetermined by 1H NMR spectroscopy. dDetermined by GLC analysis using triphenylmethane as the internal standard. eAnalytically pure endo adduct after flash column chromatography on silica gel. fDetermined by HPLC analysis using chiral stationary phases. gDienophile concentration of 0.4 M. h99% conversion after 1 day. iContamined with trace amounts of the aldol adduct. b

the diastereomeric mixture of (S,S)-11 and (S,R)-11, where δ 39.7 ppm was detected for (S,S)-5 next to three weaker resonances at δ 32.8, 7.5, and −13.5 ppm for (S,R)-5. The chemical shifts of δ 39.9 and 32.8 for these six-membered ring systems fit nicely into the scale of medium-sized cyclic, sulfurstabilized silicon cations:6,8 more deshielded silicon atom for smaller and less deshielded silicon atom for larger rings. This trend is in agreement with an analysis disclosed by Müller.18 Diels−Alder Reactions Catalyzed by the Chiral SulfurStabilized Silicon Cations. To test both the catalytic activity and ability to induce enantioselectivity, we used the novel sulfur-stabilized silicon cations (S,S)-5 and (S,R)-5 as catalysts in the Diels−Alder reaction of cyclohexa-1,3-diene (1) and chalcone (2). This cycloaddition had already served as a model reaction before (cf. Scheme 1),6,8 hence allowing for direct comparison of the new Lewis acids with the reported systems. The reactions were performed at room temperature and were stopped after 3 h (1/2 → 3, Table 1). Both (S,S)-5 and (S,R)-5

catalyzed this Diels−Alder reaction in acceptable yields.6,8 The enantioselectivity was significantly higher for (S,S)-5 than for (S,R)-5 (34% ee versus 13% ee, entries 1 and 2). 5 with S,S configuration could therefore be considered the match case, while the S,R configuration would then correspond to the mismatch combination. Not surprisingly, the enantiomeric excess obtained with the equimolar mixture (S,S)-5/(S,R)-5 was between the values for the pure diastereomers (25% ee, entry 3). Full conversion was still reached at 0 °C, but the temperature had no effect on the enantioinduction. The enantioselectivity of 34% ee induced by (S,S)-5 clearly exceeds the 11% ee achieved with (S)-4, and other sulfur-stabilized silicon cations had always furnished the cycloadduct 3 in racemic form.6,8 Encouraged by these results, we explored the chalcone scope with the more selective Lewis acid (S,S)-5 (Table 2, entries 2− 10). We had found out in an earlier dienophile screening that benzylideneacetone (30) did undergo the cycloaddition with C

DOI: 10.1021/acs.organomet.6b00548 Organometallics XXXX, XXX, XXX−XXX

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Organometallics essentially no asymmetric induction (1/30 → 31, entry 11). This result hinted that an aryl group attached to the carbonyl carbon atom is crucial for enantioinduction (entry 1 versus entry 11). To further verify this hypothesis, we synthesized several chalcone derivatives 12−19 with R2 groups of different steric demand. Chalcones 12−14 with para substitution of the aryl group (Me, tBu, and Ph) reacted with the usual efficiency, and the enantiomeric excesses measured for adducts 21−23 were higher than that for parent 3 (entries 2−4). The ee values of 53% for R2 = 4-tBuC6H4 and 55% for R2 = 4-PhC6H4 are excellent in view of the fact that these are the highest values achieved in Diels−Alder reactions of cyclohexa-1,3-diene (1) and unfunctionalized chalcones.3b In turn, substitution in the ortho position as in 15−17 had the opposite effect, resulting in slightly diminished or completely eroded enantiomeric excesses for 1/15 → 24 and 1/16 → 25, respectively, or decreased reactivity for 1/17 → 26, with adduct 26 decomposing during the purification procedure (entries 5−7). The poor outcome with 2′-methoxychalcone (16) is particularly noteworthy, as Lei and co-workers had obtained 90% ee for 2′-hydroxychalcone with their VANOL-based boron Lewis acid catalyst.3b,19 Likewise, an α-naphthyl group was detrimental to enantioinduction (1/18 → 27, entry 8). However, the corresponding chalcone derivative with a β-naphthyl group improved the enantiomeric excess back to 50% ee (1/19 → 28, entry 9). The highest enantioselectivity was achieved with a dienophile where both R1 and R2 are β-naphthyl groups: 59% ee for 1/20 → 29 (entry 10). It is worth mentioning that extension of this protocol to cinnamates11−13 failed due to ester cleavage.

Foundation (Berlin) for an endowed professorship. We thank Dr. Volker Rohde (TU Berlin) for fruitful discussions.

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(1) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2000, 2, 3517−3520. (2) Karthikeyan, M.; Kamakshi, R.; Sridar, V.; Reddy, B. S. R. Synth. Commun. 2003, 33, 4199−4204. (3) For Diels−Alder reactions of cyclohexa-1,3-diene and 2′hydroxychalcones, see the following. Racemic: (a) Cong, H.; Ledbetter, D.; Rowe, G. T.; Caradonna, J. P.; Porco, J. A. Jr. J. Am. Chem. Soc. 2008, 130, 9214−9215. Enantioselective, exploiting twopoint binding of the dienophile to the chiral Lewis acid: (b) Li, X.; Han, J.; Jones, A. X.; Lei, X. J. Org. Chem. 2016, 81, 458−468. (4) (a) Klare, H. F. T.; Bergander, K.; Oestreich, M. Angew. Chem., Int. Ed. 2009, 48, 9077−9079. (b) Schmidt, R. K.; Müther, K.; MückLichtenfeld, C.; Grimme, S.; Oestreich, M. J. Am. Chem. Soc. 2012, 134, 4421−4428. (c) Nödling, A. R.; Müther, K.; Rohde, V. H. G.; Hilt, G.; Oestreich, M. Organometallics 2014, 33, 302−308. (5) (a) Müther, K.; Fröhlich, R.; Mück-Lichtenfeld, C.; Grimme, S.; Oestreich, M. J. Am. Chem. Soc. 2011, 133, 12442−12444. (b) Müther, K.; Hrobárik, P.; Hrobáriková, V.; Kaupp, M.; Oestreich, M. Chem. Eur. J. 2013, 19, 16579−16594. (6) Rohde, V. H. G.; Pommerening, P.; Klare, H. F. T.; Oestreich, M. Organometallics 2014, 33, 3618−3628. (7) Schmidt, R. K.; Klare, H. F. T.; Fröhlich, R.; Oestreich, M. Chem. - Eur. J. 2016, 22, 5376−5383. (8) Rohde, V. H. G.; Müller, M. F.; Oestreich, M. Organometallics 2015, 34, 3358−3373. (9) The design of (S)-4 was inspired by the corresponding acetonitrile adduct reported by Helmchen and co-workers.10 That intermolecular Lewis pair enabled the cycloaddition of cyclohexa-1,3diene and 3-acryloyloxazolidin-2-one with 10% ee, while our intramolecular Lewis pair led to 24% ee in the same reaction.8 (10) Johannsen, M.; Jørgensen, K. A.; Helmchen, G. J. Am. Chem. Soc. 1998, 120, 7637−7638. (11) (a) Mathieu, B.; de Fays, L.; Ghosez, L. Tetrahedron Lett. 2000, 41, 9561−9564. (b) Tang, Z.; Mathieu, B.; Tinant, B.; Dive, G.; Ghosez, L. Tetrahedron 2007, 63, 8449−8462. (12) Sakaguchi, Y.; Iwade, Y.; Sekikawa, T.; Minami, T.; Hatanaka, Y. Chem. Commun. 2013, 49, 11173−11175. (13) Gatzenmeier, T.; van Gemmeren, M.; Xie, Y.; Höfler, D.; Leutzsch, M.; List, B. Science 2016, 351, 949−952. (14) Kubota, K.; Hamblett, C. L.; Wang, X.; Leighton, J. L. Tetrahedron 2006, 62, 11397−11401. (15) Hoshi, T.; Sasaki, K.; Sato, S.; Ishii, Y.; Suzuki, T.; Hagiwara, H. Org. Lett. 2011, 13, 932−935. (16) Corey, J. Y. J. Am. Chem. Soc. 1975, 97, 3237−3238. (17) We7 as well as Siegel and co-workers made similar observations: (a) Duttwyler, S.; Do, Q.-Q.; Linden, A.; Baldridge, K. K.; Siegel, J. S. Angew. Chem., Int. Ed. 2008, 47, 1719−1722. (b) Duttwyler, S.; Zhang, Y.; Linden, A.; Reed, C. A.; Baldridge, K. K.; Siegel, J. S. Angew. Chem., Int. Ed. 2009, 48, 3787−3790. (18) Reißmann, M.; Schäfer, A.; Panisch, R.; Schmidtmann, M.; Bolte, M.; Müller, T. Inorg. Chem. 2015, 54, 2393−2402. (19) We did not use 2′-hydroxychalcone as dienophile3b because the free phenolic hydroxy group could potentially initiate competing Brønsted acid catalysis.4b

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CONCLUSION Enantioselective Diels−Alder reactions of cyclohexa-1,3-diene (1) remain a major challenge.12 The present work is a step forward toward solving this problem. Significant enantioselectivities of close to 60% ee have been achieved for the first time with unfunctionalized chalcone derivatives as dienophiles.3b Silicon cations intramolecularly stabilized by a sulfide donor are generally sufficiently Lewis acidic to facilitate this cycloaddition,6,8 and the new dihydrosilepine-based catalyst (S,S)-5 with another binaphthyl substituent at the silicon atom is the first system to induce considerable enantioselectivity. Further optimization of this catalyst structure as well as mechanistic investigations are currently being pursued in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.6b00548. Synthetic procedures and NMR spectra of the compounds synthesized in this paper, as well as analytical data for the unknown compounds (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail for M.O.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Deutsche Forschungsgemeinschaft (Oe 249/12-1). M.O. is indebted to the Einstein D

DOI: 10.1021/acs.organomet.6b00548 Organometallics XXXX, XXX, XXX−XXX