Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Rh-Mediated Asymmetric-Transfer Hydrogenation of 3‑Substituted Chromones: A Route to Enantioenriched cis-3(Hydroxymethyl)chroman-4-ol Derivatives through Dynamic Kinetic Resolution Bin He, Phannarath Phansavath,* and Virginie Ratovelomanana-Vidal*
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PSL University, Chimie ParisTech, CNRS, Institute of Chemistry for Life and Health Sciences, CSB2D Team, 75005 Paris, France S Supporting Information *
ABSTRACT: Enantioenriched cis-3-(hydroxymethyl)chroman-4-ol derivatives were conveniently prepared by rhodium-catalyzed asymmetric transfer hydrogenation of 3formylchromones through a dynamic kinetic resolution process. The reaction proceeded under mild conditions using a low catalyst loading and HCO2H/Et3N (5:2) as the hydrogen source, delivering the reduced compounds in good yields, high diastereomeric ratio (up to 98:2 dr), and excellent enantioselectivities (up to >99% ee).
C
Scheme 1. Asymmetric Reduction of 3-Substituted Chromones
hromanoids and their derivatives found in a number of natural products are relevant targets and serve as key structural motifs thanks to their pharmacological and biological activities including antitumoral, antibacterial, antioxidant, or antiestrogenic properties.1 As such, identification of economical routes to access such compounds is highly desirable. In this context, a straightforward synthesis to enantiomerically enriched 3-substituted chromanols relies on the asymmetric reduction of 3-substituted chroman-4-one derivatives. However, to the best of our knowledge, only two examples of such transformations were reported (Scheme 1). Semeniuchenko et al. described the hydrogenation of electron-deficient alkenes by using iridium complexes and a base as co-catalyst.2 Whereas 7-methoxyisoflavone was reduced with [Ir(COD)((4S)-iPr-Phox)]BARF and a large excess of NEt3 to the enantioenriched isoflavanol derivative (12% ee) in good yield, the reaction failed to afford the expected product in the case of 3-formylchromone. On the other hand, Glorius et al. investigated the ruthenium−NHCcatalyzed hydrogenation of flavones and chromones to stereoselectively access flavanones, flavanols, chromanones, and chromanols.3 Whereas the asymmetric hydrogenation proceeded with moderate to good diastereoselectivities and high enantioselectivities for 2-substituted flavones and chromones (up to 67% de, up to 98% ee), a drop in enantioselectivity was observed with the 3-substituted regioisomer (79% de, 62% ee). As far as asymmetric transfer hydrogenation (ATH)4,5 of 3substituted chromone derivatives is concerned, no example has been reported to date. As part of our ongoing studies directed toward the development of efficient methods for the asymmetric reduction of functionalized ketones,6 we report herein the first rhodium-catalyzed asymmetric transfer hydrogenation of 3formylchromone derivatives that provides in a single operation the corresponding 3-(hydroxymethyl)chromanols in good © XXXX American Chemical Society
yields and with excellent levels of diastereo- and enantioselectivity through a dynamic kinetic resolution (DKR)7 process. We first investigated the asymmetric transfer hydrogenation of 3-formylchromone 1a to optimize the reaction conditions. When Noyori’s ruthenium catalyst (R,R)-A8 (1 mol %) was used in the presence of 5 equiv of a HCO2H/Et3N (5:2) azeotropic mixture as the hydrogen source, in CH2Cl2 at 30 °C, no traces of diol 2a could be detected after 65 h of reaction, and alcohol 3a Received: March 21, 2019
A
DOI: 10.1021/acs.orglett.9b01002 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 2. Optimization of the Reaction Parametersa
was exclusively isolated in 40% yield (Table 1, entry 1). Under otherwise identical conditions, the tethered ruthenium complex Table 1. Screening of Catalysts and Solvent Effect for the ATH of 3-Formylchromone 1aa
entry
cat.
solvent
yield of 2ab (%)
drc
eed (%)
1 2 3 4 5 6 7 8 9 10
(R,R)-A (S,S)-B (R,R)-C (R,R)-D (R,R)-D (R,R)-D (R,R)-D (R,R)-D (R,R)-D (R,R)-D
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH3CN dioxane 2-MeTHF toluene Et2O DMF
e 44 28 62 56 42 37 28 38 52
67:33 96:4 97:3 98:2 96:4 95:5 94:6 91:9 97:3
−95 99 99 98 97 97 97 99 98
entry
S/C
conc (M)
FA/TEA (5:2) (equiv)
yieldb (%)
drc
eed (%)
1 2 3 4 5 6 7 8 9 10 11
100 200 1000 10000 200 200 200 200 200 200 200
0.33 0.33 0.33 0.33 0.33 0.33 0.33 0.25 0.5 1.0 neat
5 5 5 5 3 7 10 7 7 7 7
62 62 47
97:3 97:3 99:1
99 99 99
26 74 67 72 79 84 73
90:10 97:3 98:2 97:3 97:3 98:2 98:2
98 99 99 99 99 99 99
a Conditions: The reaction was carried out on 1a (0.5 mmol) with (R,R)-D and HCO2H/Et3N (5:2) as the hydrogen source. bIsolated yield. cDetermined by 1H NMR of the crude after the ATH. d Determined by SFC analysis.
attained by using 7 equiv of the hydride donor (74%, Table 2, entry 6 vs entries 2, 5, and 7). Other hydrogen-donor sources such as HCO2Na, HCO2NH4, (HCO2)2Ca, NaH2PO2·H2O, and KOH/i-PrOH were evaluated as well (not shown in Table 2). With these reagents, however, the reaction led to either no conversion or reduction only of the aldehyde functional group to afford alcohol 3a. Besides, switching the HCO2H/Et3N ratio from 5:2 to 1:1 resulted in the formation of compound 3a only (not shown in Table 2). The last reaction parameter we considered was the concentration and we found the optimum reaction concentration of 1.0 mol·L−1 afforded a good 84% yield (Table 2, entry 10 vs 6, 8, and 9), whereas the neat reaction gave a less satisfying result (Table 2, entry 11). On the basis of the above screening, the optimized conditions were set as follows: (R,R)-D (0.5 mol %) as the precatalyst, HCO2H/Et3N (5:2) (7.0 equiv), CH2Cl2(1.0 M) at 30 °C. To better understand the reaction process, a series of control experiments were conducted. We first performed monitoring studies of the Rh-catalyzed asymmetric transfer hydrogenation of 1a under the optimized conditions (Figure 1). After 0.25 h of
a
Conditions: 1a (0.5 mmol), cat. (1 mol %), CH2Cl2 (1.5 mL), HCO2H/Et3N (5:2) (212 μL), 30 °C. The reaction was monitored by TLC or 1H NMR. bIsolated yield of 2a. With the exception of entry 2, compound 3a was formed in all cases. cDetermined by 1H NMR of the crude after the ATH. dDetermined by SFC analysis. eCompound 3a was exclusively isolated in 40% yield.
(S,S)-B9 furnished the corresponding reduced compound 2a with a moderate 44% yield, a diastereomeric ratio of 67:33 in favor of the cis compound, and an enantioselectivity of 95% ee (Table 1, entry 2). Compound 2a was produced with a lower yield by using the tethered rhodium complex (R,R)-C,10 although in this case a high dr was observed with an excellent ee (28% yield, 96:4 dr, 99% ee, Table 1, entry 3). The reaction with the parent Rh complex (R,R)-D10,11 resulted in a satisfying 62% yield with both high diastereo- and enantioselectivities (97:3 dr, 99% ee, Table 1, entry 4). With these encouraging results in hand, and using complex (R,R)-D, we then screened a variety of solvents, such as CH3CN, dioxane, 2-MeTHF, toluene, Et2O, and DMF (Table 1, entries 5−10). Although a slightly better dr value was attained in CH3CN, the yield was lower than in CH2Cl2, and none of the tested solvents outperformed the latter. Consequently, CH2Cl2 was selected as the solvent of choice for the ATH/DKR of 1a. We pursued the optimization of the reaction conditions by varying the catalyst loading, the concentration, and the amount and nature of the hydrogen source (Table 2). Identical results in terms of yield and stereoselectivity were obtained for the ATH/DKR of 1a with S/C 100 and S/C 200 (Table 2, entries 1 and 2), but lowering to S/C 1000 and S/C 10000 had a detrimental effect on the yield of 2a with no formation of the expected diol in the latter case (Table 2, entries 3 and 4). Maintaining the catalyst loading to S/C 200, we next studied the influence of the amount of the HCO2H/Et3N (5:2) mixture. From the various tested conditions, the best yield was
Figure 1. Monitoring studies of the ATH/DKR of 1a (proportions were determined by 1H NMR). B
DOI: 10.1021/acs.orglett.9b01002 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 3. Substrate Scope of the ATH/DKR of 3-Formylchromone Derivativesa
Conditions: 1a−m (0.75 mmol), (R,R)-D (0.5 mol %), CH2Cl2 (0.75 mL), HCO2H/Et3N (5:2) (446 μL), 30 °C. The reaction was monitored by TLC or 1H NMR. bIsolated yield. cDetermined by 1H NMR of the crude after the ATH. dDetermined by SFC analysis.
a
enantioinduction (97:3 dr, > 99% ee), thus supporting a DKR process. With these optimized conditions in hand, we explored the substrate scope of the reaction with a series of 3formylchromones 1a−m bearing various electron-donating or electron-withdrawing substituents on the phenyl ring (Table 3). All substrates afforded the suitable cis-diols in good yields with high dr values and excellent enantioselectivities (Table 3, entries 1−13). The absolute configurations of diols 2a and 2g were unambiguously assigned as (R,R) by X-ray crystallographic analysis. By analogy, we conjecture that the remainder of the ATH products 2 followed the same trend. The efficiency of this ATH was supported by a scale-up experiment. Under the standard conditions, a gram-scale reduction of 1g delivered the desired product 2g in 81% yield with high dr and ee values (Scheme 2). In addition, the postfunctionalization of compounds 2f and 2g was performed. After acetonide protection of 2f, biaryl derivatives 5 and 6 were readily prepared in high yields through Suzuki−Miyaura
reaction, a complete consumption of the starting material was observed with formation of products 2a, 3a, and 4a. It should be noted that the diol resulting from the reduction of the ketone functional group of intermediate 3a was not detected in this study. It appears that reduction of the aldehyde moiety and of the CC bond was fast, yielding compounds 3a and 4a with a cumulative proportion of 80% as a mixture with 2a after 0.25 h of reaction. The amount of intermediate 4a then rapidly decreased, with only traces detected after 7 h, and complete consumption was obtained after 48 h. It is worth noting that when the reaction was quenched after 0.25 h, intermediate 4a was found to be present as a racemic mixture. To confirm that the ATH of 1a proceeded through a dynamic kinetic resolution, an authentic sample of racemic 4a was prepared (see the Supporting Information) and subjected to the optimized reaction conditions. In this control experiment, the ATH of (±)-4a afforded the diol 2a in 83% yield, with a high level of diastereo- and C
DOI: 10.1021/acs.orglett.9b01002 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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Scheme 2. Scale-up Experiment and Post-functionalization Reactions
Letter
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Virginie Ratovelomanana-Vidal: 0000-0003-1167-1195 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche (MENESR), and the Centre National de la Recherche Scientifique (CNRS). We gratefully acknowledge the China Scholarship Council (CSC) for a grant to B.H. We thank G. Gontard for the X-ray analysis (Sorbonne Université, Paris).
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(1) (a) Ellis, G. P. Chromenes, Chromanones, and Chromones; Wiley: New York, 1977. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893. (c) Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges, F. Chem. Rev. 2014, 114, 4960. (d) Chandler, I. M.; McIntyre, C. R.; Simpson, T. J. J. Chem. Soc., Perkin Trans. 1 1992, 2285. (e) Maiti, A.; Cuendet, M.; Croy, V. L.; Endringer, D. C.; Pezzuto, J. M.; Cushman, M. J. Med. Chem. 2007, 50, 2799. (f) Zhao, Z.; Ruan, J.; Jin, J.; Zou, J.; Zhou, D.; Fang, W.; Zeng, F. J. Nat. Prod. 2006, 69, 265. (g) Albrecht, U.; Lalk, M.; Langer, P. Bioorg. Med. Chem. 2005, 13, 1531. (h) Farmer, R. L.; Biddle, M. M.; Nibbs, A. E.; Huang, X.; Bergan, R. C.; Scheidt, K. A. ACS Med. Chem. Lett. 2010, 1, 400. (2) Semeniuchenko, V.; Exner, T. E.; Khilya, V.; Groth, U. Appl. Organomet. Chem. 2011, 25, 804. (3) Zhao, D.; Beiring, B.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 8454. (4) For selected reviews on ATH, see: (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045. (c) Everaere, K.; Mortreux, A.; Carpentier, J.-F. Adv. Synth. Catal. 2003, 345, 67. (d) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (e) Samec, J. S. M.; Bäckvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237. (f) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300. (g) Blacker, A. J. In Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J., Ed.; WileyVCH: Weinheim, 2007; p 1215. (h) Foubelo, F.; Nájera, C.; Yus, M. Tetrahedron: Asymmetry 2015, 26, 769. (i) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621. (j) Ayad, T.; Phansavath, P.; RatovelomananaVidal, V. Chem. Rec. 2016, 16, 2754. (5) For a Ru-catalyzed enantioselective synthesis of isoflavanones by DKR, see: Qin, T.; Metz, P. Org. Lett. 2017, 19, 2981. (6) (a) Echeverria, P.-G.; Cornil, J.; Férard, C.; Guérinot, A.; Cossy, J.; Phansavath, P.; Ratovelomanana-Vidal, V. RSC Adv. 2015, 5, 56815. (b) Monnereau, L.; Cartigny, D.; Scalone, M.; Ayad, T.; Ratovelomanana-Vidal, V. Chem. - Eur. J. 2015, 21, 11799. (c) Perez, M.; Echeverria, P.-G.; Martinez-Arripe, E.; Ez Zoubir, M.; Touati, R.; Zhang, Z.; Genet, J.-P.; Phansavath, P.; Ayad, T.; RatovelomananaVidal, V. Eur. J. Org. Chem. 2015, 2015, 5949. (d) Zheng, L.-S.; Férard, C.; Phansavath, P.; Ratovelomanana-Vidal, V. Chem. Commun. 2018, 54, 283. (e) Zheng, L.-S.; Phansavath, P.; Ratovelomanana-Vidal, V. Org. Chem. Front. 2018, 5, 1366. (f) Zheng, L.-S.; Phansavath, P.; Ratovelomanana-Vidal, V. Org. Lett. 2018, 20, 5107. (7) For selected reviews on DKR, see: (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36. (b) Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 25, 447. (c) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475. (d) Ratovelomanana-Vidal, V.; Genêt, J.-P. Can. J. Chem. 2000, 78, 846. (e) Huerta, F. F.; Minidis, A. B. E.; Bäckvall, J.-E. Chem. Soc. Rev. 2001, 30, 321. (f) Pàmies, O.; Bäckvall, J.E. Chem. Rev. 2003, 103, 3247. (g) Pellissier, H. Tetrahedron 2003, 59,
coupling by using Pd(OAc)2, cataCXium A as a ligand, K2CO3 as a base, and phenyl- or 4-methoxyphenylboronic acid, respectively. Finally, diol 2g was readily converted into protected amino alcohol 7 in three steps via a Mitsunobu reaction. In summary, the operationally simple rhodium-catalyzed asymmetric transfer hydrogenation of 3-formylchromones appears to be an efficient tool for the synthesis of cis-3(hydroxymethyl)chromanol derivatives. This method confers several advantages compared to the scarce examples of asymmetric hydrogenation. The in-house developed Rh(III) complex enables the reduction under mild conditions using a low catalyst loading and HCO2H/Et3N (5:2) as the hydrogen source, delivering the reduced compounds in good yields and excellent diastereo- and enantioselectivities (up to 98:2 dr, up to >99% ee). Furthermore, the usefulness of this method was demonstrated by the efficient gram-scale asymmetric transfer hydrogenation of 1g. Finally, the 3-(hydroxymethyl)chromanols produced in this study can serve as useful scaffolds for further functionalization to access diversely substituted chromanol derivatives.
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REFERENCES
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01002. Experimental procedures, compound characterization data, NMR spectra, and SCF data for all new compounds (PDF) Accession Codes
CCDC 1896174−1896175 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. D
DOI: 10.1021/acs.orglett.9b01002 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters 8291. (h) Pellissier, H. Tetrahedron 2008, 64, 1563. (i) Pellissier, H. Tetrahedron 2011, 67, 3769. (j) Hamada, Y. Chem. Rec. 2014, 14, 235. (k) Foubelo, F.; Nájera, C.; Yus, M. Tetrahedron: Asymmetry 2015, 26, 769. (l) Echeverria, P.-G.; Ayad, T.; Phansavath, P.; RatovelomananaVidal, V. Synthesis 2016, 48, 2523. (8) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (b) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738. (9) (a) Hannedouche, J.; Clarkson, G. J.; Wills, M. J. J. Am. Chem. Soc. 2004, 126, 986. (b) Cheung, F. K. K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. Y.; Wills, M. J. Org. Chem. 2005, 70, 3188. (10) Zheng, L.-S.; Llopis, Q.; Echeverria, P.-G.; Férard, C.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V. J. Org. Chem. 2017, 82, 5607. (11) Echeverria, P.; Férard, C.; Phansavath, P.; RatovelomananaVidal, V. Catal. Commun. 2015, 62, 95.
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DOI: 10.1021/acs.orglett.9b01002 Org. Lett. XXXX, XXX, XXX−XXX
