Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Synthesis of Highly Enantioenriched Propelladienes and their Application as Ligands in Asymmetric Rh-Catalyzed 1,4-Additions Tommaso Pecchioli and Mathias Christmann* Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
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S Supporting Information *
ABSTRACT: The first synthesis of highly enantioenriched [4.3.3]propelladienes is reported. The novel bridged bicyclo[3.3.0] dienes were applied as steering ligands in the rhodium-catalyzed asymmetric arylation of cyclic enones. The catalytic system showed high catalytic activity, and the 1,4-adducts were obtained in good to excellent yields (46−99%) with enantioselectivities up to 96% ee.
C
Scheme 1. Approaches to the Propelladienes
hiral dienes have recently emerged as powerful new ligands in asymmetric catalysis.1 Since the pioneering works of the groups of Hayashi2 and Carreira,3 a variety of olefin ligands have been used successfully in asymmetric transition-metal-catalyzed transformations.4 So far, their structural diversity has been limited to planar chiral,5 acyclic,6 and bicyclic dienes,7 with the latter ones leading to the best performance. We speculated that the presence of transannular bonds in rigid polycyclic ligands could have a beneficial influence on the catalytic behavior of the active metal complex. Nevertheless, access to polycyclic chiral dienes in enantiomerically enriched form is still limited,8 probably due to synthetic challenges. Among polycyclic molecules, propellanes consist of a tricyclo[m.n.o.0] architecture9 that embeds three rings cojoined by a central C−C bond.10 Paquette et al. prepared and demonstrated the utility of achiral [4.4.2]propella-3,11diene as a chelating diene by the formation of a molybdenum complex (Scheme 1a).11 Recently, our group developed a general asymmetric route to carbocyclic propellanes.12 Inspired by the work of Paquette, we decided to implement our approach in the preparation of enantiomerically enriched [4.3.3]propelladienes (PPDs) (Scheme 1b). The use of bicycloocta-2,6-dienes as steering ligands in rhodium-catalyzed arylations was introduced by the groups of Hayashi,7c Lin,13 and Laschat.14 In order to design more efficient ligands, variations on length of the transannular connection and on topology of the diene substitution were extensively investigated (Scheme 2). A comparative DFT analysis, carried out by Kantchev,15 rationalized the effect on enantioselectivity of such modifications. The study finally led to the synthesis of highly selective 3,7-disubstituted bicyclo[3.3.0]octa-2,6-dienes.16 This type of diene induces the best cooperation between crossed coordination to the metal center and steric repulsion of the substituents.15a On the other hand, the effect of an additional alkyl bridge on bicycloocta-2,6-dienes has not been examined. In this work, we expand the diversity of this family of steering ligands by the disclosure of novel tricyclic representatives. The impact of the geometrical features of PPDs on catalysis was then © XXXX American Chemical Society
experimentally evaluated for the first time using the Rhcatalyzed 1,4-arylations of cyclic enones. Our synthesis of the PPDs commenced with the preparation of the Hajos−Parrish ketone derivative 2 in three steps from commercially available cyclopentane-1,3-dione (1) (Scheme 3a).12a Enone 2 was obtained in >99% ee after a simple recrystallization on gram scale. Conjugate addition of a highorder vinyl cuprate to 2 forged the second quaternary center of 3 in 49% yield. Subsequent ring-closing metathesis furnished propellenedione 4 in nearly quantitative yield. The less hindered C3 carbonyl was sequentially reduced to investigate the influence of the oxygen function on the bridge of the final ligands. The C3-carbonyl group of 4 was selectively reduced to alcohol 5 in 83% yield using L-Selectride (Scheme 3b).12a Received: July 15, 2018
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DOI: 10.1021/acs.orglett.8b02204 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Family of the Octa-2,6-diene Ligands17
symmetric tricycle 13 by application of a Clemmensen reduction. The reaction proceeds via in situ acetal cleavage and subsequent carbonyl reduction to deliver tricycle 13, which to the best of our knowledge, represents the first example of an enantiomerically enriched PPD hydrocarbon. With the five new PPD ligands, [4.3.3]propella-7,10-dienes or tricyclo[4.3.3.0]dodeca-7,10-dienes9 (7, 9, 10, 12, and 13) in hand, we tested their performance as chiral ligands in the rhodium-catalyzed asymmetric 1,4-addition of arylboronic acid to cyclic enones. We selected cyclohex-2-enone (14) as a model acceptor for the conjugate addition. The desired diene− rhodium catalyst was prepared in situ starting from the readily available [Rh(C2H4)2Cl]2. An initial loading of 3.0 mol % (with respect to Rh) was chosen to evaluate the performance of the synthesized PPDs (Table 1).2 All of the prepared ligands led to excellent yields for 15a (complete conversion within 5 min as indicated by thin-layer chromatography control). The ligands with unsubstituted diene moiety provided excellent enantioselectivities (93% ee; Table 1, entries 1, 3−5), whereas substituted 10 (entry 2) was clearly inferior. The oxygen function on the bridge and the chosen protecting groups had a minor influence on the catalytic performance. Ligand (1R,6S)-12 was then selected for our studies due to its shorter preparation (three steps from 9). The rhodium−ethylene precatalyst [Rh(C2H4)2Cl]2 was submitted to an olefin-exchange reaction with diene 12 to yield the PPD−Rh complex (see the Supporting Information (SI)). At this point, the catalyst loading was decreased to assess the activity of our catalytic system in the 1,4-arylation of 14 (Table 2).
Subsequently, the hydroxyl group of 5 was silylated using TBSOTf or the more sterically demanding TIPSOTf in good yields. The second alkene was introduced by conversion of the C7-carbonyl groups of 6 and 8 to the corresponding enol triflates, followed by palladium-catalyzed reductions to yield dienes 7 and 9. Suzuki coupling of the triflate derived from ketone 8 with phenylboronic acid gave substituted diene 10. Thus, O-silylated dienols 7, 9, and 10 were obtained in four steps starting from propellendione 4. Alternatively, diketone 4 was transformed into dioxolane 11 (Scheme 3c). The diene moiety was generated using the above-discussed triflation/reduction sequence to give PPD 12. All reactions toward diene 12 could be performed on a gram scale and resulted in the isolation of more than 800 mg of the final material. Finally, PPD 12 was converted into the C2-
Scheme 3. Synthesis of Highly Enantioenriched PPDs 7, 9, 10, 12, and 13
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DOI: 10.1021/acs.orglett.8b02204 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 3. Substrate Scopea
Table 1. PPD Ligand Screening in the Rhodium-Catalyzed Asymmetric Arylation of Cyclohex-2-enone (14) with Phenylboronic Acid To Give 15aa
entry
ligand
yieldb (%)
eec (%)
1 2 3 4 5
9 10 7 12 13
97 94 97 98 96
93 21 93 93 93
entry d
1 2 3 4 5e 6e 7 8 9 10 11 12 13 14
a
Reaction conditions: enone 14 (0.350 mmol, 1.0 equiv), PhB(OH)2 (0.700 mmol, 2.0 equiv), aq KOH (1.5 M; 0.175 mmol, 0.5 equiv). b Isolated yield. cDetermined by GC analysis on a chiral column.
Table 2. Catalyst Loading Investigationa
enone
Ar−B(OH)2
prod
yieldb (%)
eec (%)
14 14 14 14 14 14 14 14 14 14 16 16 16 16
C6H5 4-OMe−C6H4 4-F−C6H4 4-Br−C6H4 4-CO2Me−C6H4 4-Me−C6H4 3-Br−C6H4 3-CF3−C6H4 2-Cl−C6H4 2-Me−C6H4 C6H5 4-OMe−C6H4 4-F−C6H4 4-Br−C6H4
15a 15b 15c 15d 15e 15f 15g 15h 15i 15j 17a 17b 17c 17d
99 >99 96 93 90 79 83 95 93 92 46 >99 96 76
93 94 93 94 96 93 96 96 84 38 74 68 70 63
a
entry
Rh (mol %)
yieldb (%)
eec (%)
1 2 3 4d
1 0.5 0.25 0.1
>99 98 96 33
93 93 93 93
Reaction conditions: 14 or 16 (0.350 mmol, 1.0 equiv), ArB(OH)2 (0.700 mmol, 2.0 equiv), aq KOH (1.5 M; 0.175 mmol, 0.5 equiv). b Isolated yields. cDetermined by GC analysis on a chiral column. d Performed on 1.00 mmol scale. e(ArBO)3 (0.66 mmol, 2.0 equiv B) was used as donor.
In summary, we have accomplished the first synthesis of a series of enantiomerically enriched [4.3.3]PPDs possessing a bicycloocta-2,6-diene moiety. The PPD ligands showed excellent catalytic efficiency in the rhodium-catalyzed asymmetric arylation of cyclic enones. In the substrate scope, good to excellent levels of asymmetric induction typical for the use of unsubstituted bicyclo[3.3.n] dienes were maintained. Application in catalysis of the tricyclic PPD ligands revealed a substantial beneficial effect on turnover frequency when compared to previous systems based on bicyclic analogues. We hope that our findings will promote future computational and experimental investigations on the effects of rigid polycyclic scaffolds in asymmetric catalysis. Further studies will be focused on understanding the active rhodium complex and potential catalyst deactivation pathways in molecular detail.
a
Reaction conditions: 14 (0.350 mmol, 1.0 equiv), PhB(OH)2 (0.700 mmol, 2.0 equiv), aq KOH (1.5 M; 0.175 mmol, 0.5 equiv). bIsolated yield. cDetermined by GC analysis on a chiral column. dThe reaction was conducted for 2 h.
The complex loading was reduced from 1 to 0.25 mol % (Table 2, entries 1−3) without affecting reaction time, yield, and selectivity (complete conversion for 14 was achieved within 5 min as indicated by thin-layer chromatography control). Further decrease of the catalyst loading (0.1 mol %) gave a reduced yield of 33% for the arylated product 15a (Table 2, entry 4). Our system showed a turnover frequency (TOF of 2.3 × 103 h−1 at 25 °C) superior to those exhibited by the reported catalytic systems based on bicyclo[3.3.n] ligands (see the SI for a detailed comparison). Finally, the scope of the asymmetric arylation was investigated by the addition of different phenylboronic acids to 6- and 5-membered cyclic enones (Table 3). Cyclohex-2-enone (14) gave good to excellent yields for the desired products 15a−j (Table 3, entries 1−10). The presence of para- and meta-substituents on the boronic acids was well tolerated and the adducts were isolated in high enantioselectivities (93−96% ee; Table 3, entries 2−8). The use of sterically hindered ortho-substituted donors led to decreased selectivity (Table 3, entries 9 and 10). In particular, addition of 2-tolylboronic acid to 14 furnished ketone 15j in 38% ee. Arylations with cyclopent-2-enone (16) occurred more sluggish in terms of yields and asymmetric inductions (Table 3, entries 11−14). The latter effect is in accordance with those observed by Lin18 and Stončius17e in the use of unsubstituted bicyclo[3.3.0] and [3.3.1] dienes as steering ligands. In our hands, cyclohept-2-enone failed to react even with electronrich boronic acids.
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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.orglett.8b02204. Experimental procedures and characterization for PPD ligands and rhodium−12 complex. General procedures for the 1,4-addition and NMR data for adducts 15a−j and 17a−d. NMR spectra and GC chromatograms (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Mathias Christmann: 0000-0001-9313-2392 C
DOI: 10.1021/acs.orglett.8b02204 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Notes
(15) (a) Kantchev, E. A. B. Chem. Sci. 2013, 4, 1864−1875. (b) Qin, H. L.; Chen, X. Q.; Shang, Z. P.; Kantchev, E. A. Chem. - Eur. J. 2015, 21, 3079−3086. (16) (a) Muhlhauser, T.; Savin, A.; Frey, W.; Baro, A.; Schneider, A. J.; Doteberg, H. G.; Bauer, F.; Kohn, A.; Laschat, S. J. Org. Chem. 2017, 82, 13468−13480. (b) Melcher, M.-C.; Rolim Alves da Silva, B.; Ivšić, T.; Strand, D. ACS Omega 2018, 3, 3622−3630. (17) (a) Otomaru, Y.; Kina, A.; Shintani, R.; Hayashi, T. Tetrahedron: Asymmetry 2005, 16, 1673−1679. (b) Feng, C. G.; Wang, Z. Q.; Tian, P.; Xu, M. H.; Lin, G. Q. Chem. - Asian J. 2008, 3, 1511−1516. (c) Shintani, R.; Ichikawa, Y.; Takatsu, K.; Chen, F.-X.; Hayashi, T. J. Org. Chem. 2009, 74, 869−873. (d) Gosiewska, S.; Raskatov, J. A.; Shintani, R.; Hayashi, T.; Brown, J. M. Chem. - Eur. J. 2012, 18, 80−84. (e) Rimkus, R.; Jurgelėnas, M.; Stončius, S. Eur. J. Org. Chem. 2015, 2015, 3017−3021. (18) Feng, C. G.; Lin, G. Q.; Xu, M. H.; Shao, C.; Wang, Z. Q. Org. Lett. 2008, 10, 4101−4104.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Umicore for donation of the metathesis catalyst. Professors C. Tzschucke and P. Heretsch (Freie Universität Berlin) are gratefully acknowledged for helpful discussions. We thank C. Groneberg (Freie Universität Berlin) for assistance with the quantitative GC analysis.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b02204 Org. Lett. XXXX, XXX, XXX−XXX
