Letter pubs.acs.org/journal/ascecg
Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Exploration of a Novel, Enamine-Solid-Base Catalyzed Aldol Condensation with C‑Glycosidic Pyranoses and Furanoses Tamara M. de Winter,† Yanna Balland,† Arwen Evenstar Neski,† Laureǹ e Petitjean,† Hanno C. Erythropel,† Magali Moreau,‡ Julien Hitce,§ Philip Coish,† Julie B. Zimmerman,† and Paul T. Anastas*,†,∥
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†
Center for Green Chemistry & Green Engineering at Yale and School of Forestry and Environmental Studies, Yale University, 195 Prospect Street, New Haven, Connecticut 06511, United States ‡ L’Oréal Recherche & Innovation, 133 Terminal Avenue, Clark, New Jersey 07066, United States § L’Oréal Research & Innovation, 30 rue Maurice Berteaux, 95500 Le Thillay, France ∥ Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, United States S Supporting Information *
ABSTRACT: A variety of unprotected C-glycosidic ketones were employed in a novel enamine-solid-base catalyzed (ESBC) aldol condensation to expand the scope and scalability of a previously reported reaction. The starting ketones were obtained from unprotected pyranoses and furanoses following Lubineau’s method via a Knoevenagel condensation. The aldol condensation reaction of the C-glycosidic ketones was performed with a nontoxic and abundant amino acid, L-proline, along with magnesium oxide (MgO) as a recyclable and sustainable catalyst. The enamine-solid-base catalyzed aldol condensations provided the corresponding (E)-α,β-unsaturated ketones in excellent isolated yields (91−100%). KEYWORDS: Aldol condensation, C-glycosides, Solid base catalysis, Sugars, L-Proline, Magnesium oxide, Green chemistry and methodology, Heterogeneous catalysis
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INTRODUCTION
aldehydes that feature both electron-rich and electron-poor substituents, as well as sterically hindered groups.9 Moreover, our methodology utilizes a recyclable, heterogeneous catalyst and nontoxic L-proline, providing a greener, cheaper, and safer alternative to previous methods that also eliminates the use of protecting groups.10,6 The aim of the present study was to develop the versatility of the ESBC aldol condensation by investigating the reactivity of a variety of unprotected Cglycosidic ketones, A, with benzaldehyde (B, R = H) as the coupling partner (Scheme 1). The present study further defines the scope of the method and provides practitioners with a green and efficient method with broad utility. Herein, we report both the synthesis of C-glycosidic ketones, A, and their subsequent use in the enamine-solid-base catalyzed aldol condensation reactions to form C.
There is an increasing interest in both synthetic and natural Cglycosides as demonstrated by their use in extensively academic and industrial applications including pharmaceuticals and even cosmetics.1−4 Despite the broad interest, most of the synthetic routes to C-glycosides are hampered with protecting group manipulations.1,4 More recent chemical methods, however, have focused on the derivatization of C-glycosides without inherently inefficient protecting group strategies that lower atom economy.5−9 We have recently reported a novel route to C-glycosides that applies the Principles of Green Chemistry.9 The method features an enamine-solid-base catalyzed (ESBC) aldol condensation of C-glycosidic ketone, A, with aromatic aldehydes, B, for the preparation of a wide variety of aromatic C-glycosides, C, in excellent yields (Scheme 1). The ESBC methodology is applicable to a wide range of aromatic
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EXPERIMENTAL SECTION
Representative Synthesis of C-Glycosidic Ketones, 1. A solution of sodium hydroxide (NaOH) (3.33 g, 83.2 mmol, 1.5 equiv) in methanol (MeOH) (20 mL, 4.2 M) was slowly added to a solution containing D-glucose (10 g, 55.5 mmol) and pentane-2,4-dione (6.70 g, 66.9 mmol, 1.2 equiv) in MeOH (23 mL, 2.41 M). The reaction was stirred at 50 °C for 2 h. After complete conversion (shown by TLC), the reaction was cooled using an ice-bath, followed by
Scheme 1. General Reaction for the Synthesis of Aromatic Linear C-Glycosidic Compounds Via the Enamine-SolidBase Catalyzed Aldol Condensation Reaction
Received: June 1, 2018 Revised: July 26, 2018 Published: July 27, 2018 © XXXX American Chemical Society
A
DOI: 10.1021/acssuschemeng.8b02535 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Letter
ACS Sustainable Chemistry & Engineering Table 1. C-Glycosidic Ketones 1−10 Obtained from Unmodified Sugars, D, through a Knoevenagel Condensation
sugar
n = 0 or 1
R1
R2
R3
R4
R5
R6
R7
R8
R9
product
D-glucose D-xylose D-mannose L-rhamnose D-fructose D-ribose D-galactose L-arabinose D-arabinose
1 1 1 1 0 0 1 1 1
H H H H CH2OH H H H H
H H OH H OH H H H OH
OH OH H OH H OH OH OH H
OH OH OH H N/Aa N/A OH OH H
H H H OH N/A N/A H H OH
H H H OH H H OH OH H
OH OH OH H OH OH H H OH
CH2OH H CH2OH H CH2OH CH2OH CH2OH H H
H H H CH3 H H H H H
1 2 3 4 5 6 and 7 8 9 10
a
N/A: not applicable.
acidification to pH 3 with hydrochloric acid (HCl) (6.8 mL, 83.2 mol, 37 wt %/Nt). The product was concentrated by rotatory evaporation, followed by desalination using ethanol (EtOH). When needed (determined by proton nuclear magnetic resonance, 1H NMR), the product was purified by column chromatography on silica gel using the appropriate eluent system (either 15:4:1 EtOAc:MeOH:H2O or 9:1 DCM:MeOH; DCM, dichloromethane). The product yield of nonulose, 1, was near quantitative. Representative Procedure for the Synthesis of (E)-α,βUnsaturated Glycosidic Ketones, 11−20. Following the procedure previous reported by our lab,9 one of the C-glycosidic ketones, 1−10, (nonulose, 1, 0.5 g, 2.27 mmol), L-proline (0.2614 g, 2.27 mmol, 1 equiv), magnesium oxide (MgO) (0.05 g, 10 wt %), and an internal standard, biphenyl (17.5 mg, 0.113 mmol, 0.05 equiv), were added to a 4 dram vial equipped with a Teflon coated magnetic stir bar. Methanol (5 mL) was added, and the resulting solution was stirred rapidly until dissolution. Once dissolved a small aliquot was taken for quantitative 1H NMR analysis. Subsequently, benzaldehyde (2.71 mmol, 1.2 equiv) was added to the reaction mixture; the reaction was heated to 50 °C and monitored by liquid chromatography coupled with a refractive index detector (LC-RI) until completion. Upon completion, the reaction was stopped, and the mixture was filtered using a glass fritted funnel to remove the solidbase catalyst MgO. The catalyst was rinsed with methanol in triplicate, the filtrate collected and concentrated by rotatory evaporation. The crude reaction mixture was analyzed by 1H NMR to confirm the conversion of the C-glycosidic ketone. The resulting mixture was purified by a silica gel plug by first washing with 100% DCM, followed by 9:1 DCM:MeOH to elute the product. Concentration of the eluate provided a 91% isolated yield of product.
related to starting sugar employed in each reaction. That is, we obtained the corresponding tetrahydropyranyl C-glycosides from pyranoses such as D-glucose, and tetrahydrofuranyl Cglycosides from furanoses. For example, when D-fructose was used, we obtained the furanose 5, previously unreported. DRibose was the only compound for which both the pyranose and furanose were observed in a 7:3 ratio under our conditions. A similar result has been reported by Wang et al.5 and by Riemann et al.12 Even though the relative stereoselectivities of the sugar moieties were not determined by NMR a single diastereoisomer was seen. Once the C-glycosidic ketones 1−10 were obtained, we were ready to explore the scope of the ESBC aldol condensation reaction. Following our previously published procedure, we employed 10 wt % of magnesium oxide (MgO) as the solid base catalyst (SBC), with 1 equiv of L-proline at 50 °C in methanol.9 Due to the high hygroscopicity of the Cglycosidic ketones 1−10, an internal standard, biphenyl (0.05 equiv), was added to the reaction mixtures in order to quantify the exact amount of C-glycosidic ketone (1−10) added to each reaction via 1H NMR spectroscopy. It should also be noted that, in our previous study, we showed that the nonactivated MgO (Sigma-Aldrich, 98% ACS grade) worked as well as the activated MgO (calcinated at 900 °C for 3 h) for the ESBC aldol condensation of C-glycosidic ketones.9 As such, we had continued our investigation of the methodology with the nonactivated MgO. As shown in Table 3, the condensation reactions with ketones 2−10 performed quite well and led to complete conversion (>95%) of our starting materials to the desired (E)α,β-unsaturated ketones 11−20. Quantitative yields of products 11−20 were obtained which compared well with our previously reported yield of 91% for product 11.9 In entry 6, the aldol condensation reaction was performed with a 7:3 mixture of pyranose, 6, and furanose, 7, respectively, that was derived from D-ribose, and the ratio of corresponding products, 16 and 17, remained unchanged. It is notable that the reaction conditions provided high yields of desired products from a variety of unprotected C-glycosidic ketones, including furanyl and pyranyl ketones with different substitution patterns. These results indicate that the reaction proceeds efficiently with a variety of unprotected alcohols. Our method is in accordance with Green Principle No. 8 that states “Unnecessary derivatization should be minimized or avoided, if
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RESULTS AND DISCUSSION The C-glycosidic ketones (1−10) were prepared via a one-pot reaction sequence that included a Knoevenagel condensation reaction that followed a procedure similar to that of Cavezza et al.8 with minor changes (Table 1). In our preparation, sodium hydroxide (NaOH) and methanol (MeOH) were used as the base and solvent, respectively, rather than sodium bicarbonate (NaHCO3) and water. The reaction solvent was changed to methanol from water due to the high hygroscopicity of our product. Furthermore, the reaction was heated to 50 °C rather than 90 °C.11,8 With these changes, the desired products were obtained within 2−5.25 h instead of 12 h. However, in some cases, lower isolated yields than those reported by Cavezza et al.8 and Rodrigues et al.11 were obtained due to product loss if the chromatographic step was required (Table 2). As expected, we observed that the ring size of the product(s) was directly B
DOI: 10.1021/acssuschemeng.8b02535 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Letter
ACS Sustainable Chemistry & Engineering Table 2. Synthesis and Yields of the C-Glycosidic Ketones 1−10 Obtained through the Knoevenagel-Type Condensation
Table 3. Enamine-Solid-Base Catalyzed Aldol Condensation Reaction of C-Glycosidic Ketones with Benzaldehydea
entry
ketone
time
NMR conversionb
1 2 3 4 5 6 7 8 9
1 2 3 4 5 6 and 7 8 9 10
6.5 h 17 h 17 h 17 h 17 h 13.5 h 15.6 h 15.7 h 15.7 h
>95% >95% >95% >95% >95% >95% >95% >95% >95%
yieldc of product 11 12 13 14 15 16 and 17 18 19 20
91%d quantitative quantitative quantitative quantitative quantitative quantitative 98% quantitative
a
Reaction conditions: All reactions were carried out in MeOH (0.45 M) with 1.2 equiv benzaldehyde, 10 wt % MgO, 1 equiv L-proline at 50 °C.9 The reactions were monitored by LC-RI until completion and confirmed by 1H NMR. bAn internal standard, biphenyl, was used for the quantification of starting material. Values represent conversion of starting material, 1−10, to desired product. No undesired products formed. cIsolated product yields. dPreviously reported.9
Figure 1. Investigation of the Effect of MgO Loading (wt %) on the Aldol Condensation of Nonulose, 1, with Benzaldehyde at 50 °C in Methanol.
a
Reaction conditions: All reactions were carried out in MeOH (1.3 M) with the indicated sugar, 1.5 equiv NaOH, and 1.2 equiv pentane2,4-dione at 50 °C. The reactions were monitored by TLC until completion. Stereoselectivity was not determined. bIsolated yields.
optimal. It should be noted that we had previously shown that the MgO catalyst can be recycled up to 5× before there is a reduction in activity.9 Finally, a proposed mechanism for the enamine-solid-base catalyzed aldol condensation is shown in Scheme 2. From
possible, because such steps require additional reagents and can generate waste.”13 Subsequently, we engaged an exploration of the effect of catalyst loading on the outcome of our reaction. We proceeded by employing our standard conditions for the aldol condensation of 1 with benzaldehyde, 1 equiv of L-proline and varied the loading of MgO catalyst from 10 to 5, 2, 1, and to 0.5 wt % (Figure 1). The reaction times were quantitatively determined by liquid chromatography coupled with refractive index (LC-RI). As expected, the reactions with the higher loadings of MgO (10 and 5 wt %) were the fastest, and the conversion was complete within 5 h. As the catalyst loading was reduced to 1.0 and 0.5 wt %, the initial reaction rates slowed; the time to reach completion doubled to 10 h. The result demonstrates that 5−10 wt % loading of catalyst is
Scheme 2. Proposed Mechanism for the Enamine-SolidBase Catalyzed Aldol Condensation Reaction
C
DOI: 10.1021/acssuschemeng.8b02535 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Letter
ACS Sustainable Chemistry & Engineering previous experiments discussed by de Winter et al.9 it was shown that no reaction occurred when only MgO or just Lproline were used to catalyze the Aldol condensation. Thus, it is believed that there is a synergetic effect when both catalysts are used together, such that, upon the formation of the imine by L-proline, the methyl group becomes activated for deprotonation by MgO, which results in the formation of the enamine, C. This agrees with that reported in the literature5,14,15 which suggests that the formation of the enamine is crucial for the reaction to proceed.14 Additionally, Wang et al.5 have successfully isolated a derivative of intermediate D, further supporting the proposed mechanism. During this investigation we wanted to explore the scalability of this methodology in order to determine its practicality for an industrial application. We scaled our reaction by 20× by performing a 10 g reaction with octulose, 2, and 1.1 equiv benzaldehyde in the presence of 1 equiv L-proline and only 5 wt % of our catalyst, MgO. Gratifyingly, the reaction proceeded with complete conversion after 15 h as determined by LC-RI and confirmed by 1H NMR. Purification by a silica gel plug was necessary to remove the organocatalyst, L-proline, and the excess benzaldehyde. A quantitative isolated yield (13 g) of our desired product, 9, was obtained.
Notes
The authors declare no competing financial interest.
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CONCLUSION We have demonstrated the efficiency of the ESBC aldol condensation reaction with a variety of C-glycosidic ketones that were derived from unprotected sugars. The condensation reactions provided high yields (91−100%) of the desired (E)α,β-unsaturated ketones. The reaction was shown to be tolerant of the unprotected alcohols within the sugar moiety. Furthermore, we have shown that this new methodology can be scaled, and a reaction performed on a 10 g of starting ketone provided a quantitative yield of the desired (E)-α,βunsaturated ketones.
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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/acssuschemeng.8b02535.
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REFERENCES
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General synthesis for C-glycosidic ketones 1−10 and (E)-α,β-unsaturated ketones 11−20, along with their respective 1 H and 13 C NMR and mass spectra characterization (PDF)
AUTHOR INFORMATION
Corresponding Author
*Phone: 1-203-436-5127. E-mail:
[email protected]. ORCID
Tamara M. de Winter: 0000-0002-5727-3881 Laurène Petitjean: 0000-0001-7730-6655 Hanno C. Erythropel: 0000-0003-3443-9794 Julie B. Zimmerman: 0000-0002-5392-312X Paul T. Anastas: 0000-0003-4777-5172 Author Contributions
All the authors contributed equally. Funding
The authors would like to gratefully acknowledge financial support from L’Oréal. D
DOI: 10.1021/acssuschemeng.8b02535 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
