Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Divergent Entry to C‑Glycosides from Unprotected Sugars Marie-Céline Frantz,*,† Sébastien Dropsit-Montovert,† Florence Pic,† Amélie Prévot-Guéguiniat,† Clément Aracil,‡ Yudi Ding,† Magali Lima,† Francisco Alvarez,† Susana Ramos,† Lisheng Mao,§ Long Lu,§ Jinzhu Xu,† Xavier Marat,† and Maria Dalko-Csiba† †
L’Oréal Research & Innovation, 1 av. Eugène Schueller, 93600 Aulnay-sous-Bois, France L’Oréal Research & Innovation, 30 bis rue Maurice Berteaux, 95500 Le Thillay, France § Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China ‡
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S Supporting Information *
ABSTRACT: An efficient, divergent, and straightforward access to novel C-glycosides has been developed, namely, α-hydroxy carboxamide and carboxylic acid derivatives, via a green and scalable process from unprotected carbohydrates. The method involves condensation of 1,3-dimethylbarbituric acid with unprotected sugars followed by subsequent barbiturate oxidative cleavage in the same pot. Further expanding of the chemistry led to the development of efficient entries to diastereoisomerically pure C-glycosyl-α-hydroxy esters or amides through nucleophilic attack on a readily available and versatile key lactone intermediate. friendly environmental processes (second pillar), yielding final products with enhanced chances to have favorable environmental impact and human safety profile (third pillar). Based on these considerations, the development of new sugar derivatives is clearly key to many areas, including the cosmetic industry. Among all possible carbohydrate derivatives, Cglycosides are especially appealing due to their greater chemical and metabolic stability compared to that of O-glycosides. However, classical methods to access such compounds are quite tedious in most cases because they usually rely on activation of the anomeric position that often requires the protection of the hydroxyl groups.1a,4 More attractive strategies for the selective functionalization of the anomeric position rely on the use of the aldehyde moiety from unprotected sugars. Representative examples include the Lubineau reaction with 1,3-diketones,5 which was used as a key step for the synthesis of L’Oréal’s blockbuster Pro-Xylane,2d the condensation between aldoses and barbituric acid derivatives6 or Meldrum’s acid,7 the Horner−Wadsworth−Emmons reaction between unprotected mono/disaccharides and β-keto-phosphonates,8 or the recently reported elegant organocatalyzed cascade reactions between unprotected carbohydrates and ketones.9−11 Despite these developments, limitations still remain, notably in terms of C-glycosides accessible through these methods, versatility, and structural diversification. With the strong commitment to sustainability of our group and successful development of sugar-derived cosmetic ingredients such as Pro-
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n addition to their availability, carbohydrates are valuable and versatile building blocks that have notably been used for a variety of industrial applications.1 In the cosmetic industry, they are commonly utilized as active ingredients in skin and hair care products. Representative examples include alkylpolyglucosides (APG, e.g., 1) for cleansing,2a hyaluronic acid 2 for hydration,2b and rhamnose 32c or Pro-Xylane 42d for antiaging (Figure 1). In
Figure 1. Representative sugar derivatives from the cosmetic industry.
addition to their biological and physicochemical functions in living organisms, carbohydrate derivatives are also of interest in many aspects, especially in terms of sustainable chemistry. Indeed, the development of such compounds complies with the three pillars of Green Chemistry:3 sugars being renewable raw materials (first pillar), the use of which eases the development of © XXXX American Chemical Society
Received: February 21, 2019
A
DOI: 10.1021/acs.orglett.9b00666 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Xylane, the development of new, sustainable, cost-efficient, and versatile processes for the synthesis of new C-glycosides is of great importance, and we report herein some of our efforts in these directions. The present chemical approach, depicted in Scheme 1, is based on the direct condensation of barbituric acid with
Scheme 3. Proposed Mechanism for the Oxidative Cleavage of Glucose Barbiturate 6a
Scheme 1. Overview of Our Strategy To Access Novel CGlycosides
unprotected sugars 5, yielding C-glycosyl barbiturates 6.6 Despite the efficiency and robustness of this reaction, its synthetic potential, however, remains under-exploited.12 The barbiturate moiety indeed offers an interesting starting point for structural diversification that has clearly been overlooked and that could provide efficient entries to novel C-glycosides 7 through oxidative cleavage of the barbiturate. Based on this strategy, these studies were initiated by examining the direct oxidative cleavage of the C-5 monosubstituted barbiturate core, which has never been tried so far to our knowledge.6,12 D-Glucose 5a, the most common sugar, was selected as a model substrate and condensed with dimethylbarbituric acid.6 Whereas the in situ reaction of the intermediate sodium barbiturate with sodium hydroxide was found to be inefficient, its reaction with aqueous hydrogen peroxide at 60 °C interestingly led to α-hydroxyamide 7a, a compound that was isolated in 31% yield as a mixture of only two diastereoisomers (Scheme 2). The two-step synthesis of a β-methylamide C-
with either sodium hydroxide alone (33%) or in combination with hydrogen peroxide (56%).14 In addition, there are literature precedents of oxidation of barbituric acids to hydroxylated derivatives related to 8, as well as of alkaline hydrolysis of such 5hydroxy barbiturates to oxazolidinediones related to 11.15 It is worth mentioning that we could successfully apply for the first time this procedure to C-glycoside derivatives, and that all consecutive steps could be performed in a one-pot operation. Stimulated by such results, we then decided to implement this high-value and efficient method to a sugar of great interest, Dxylose 5b, while simultaneously investigating the scale-up of the process. Interested in a further structural diversification, a subsequent alkaline hydrolysis was implemented in an attempt to directly obtain α-hydroxy acid 7b without isolation of any intermediates. As shown by results summarized in Scheme 4, this strategy turned out to be quite fruitful and enabled the isolation of the desired acid 7b in 49% yield, as a mixture of two
Scheme 2. Condensation of Dimethylbarbituric Acid and Oxidative Cleavage: Synthesis of Amide 7a in Two Steps from Unprotected D-Glucose
Scheme 4. Condensation of Dimethylbarbituric Acid with Subsequent Oxidative Cleavage/Hydrolysis: Synthesis of Acid 7b in Three Steps from Unprotected D-Xylose on a 225 g Scale and Further Cyclization to Lactones 13 and 13′ glycoside relying on a green procedure from an unprotected sugar is particularly appealing, especially when compared to literature precedents that involve multistep sequences.13 From a literature review and experimental observations, the mechanism depicted in Scheme 3 was hypothesized for the oxidative cleavage of the barbiturate moiety. The electron-rich sodium barbiturate 6a would be first oxidized by hydrogen peroxide to form the 5-hydroxy intermediate 8. The barbituric moiety would then be hydrolyzed to 9 which, upon decarboxylation, would yield 10. Further cyclization of the hydroxyl group onto the N-acylurea in 10 would afford oxazolidinedione 11 whose final basic hydrolysis would account for the formation of methyl amide 7a. This mechanism is actually supported first by the fact that oxazolidinedione 11, which could be isolated through an alternative oxidative cleavage procedure displaying slower kinetics, was shown to be hydrolyzed to 7a upon treatment B
DOI: 10.1021/acs.orglett.9b00666 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
deacetylation with methanolic ammonia was favored to avoid using an excess of the amino acid. Novel C-glycosides 7e and 7e′ could be obtained in fair overall yields by simple trituration of the crude mixtures in acetone or methanol. In conclusion, an efficient, high value, divergent, scalable, and green process is reported for the synthesis of β-configured αhydroxy-β-carboxamide/β-acid C-glycosides, relying on two or three simple sequential steps and starting from readily available and renewable, unprotected carbohydrates. Further transformation of the xylose-derived carboxy C-glycoside led to highly versatile diastereoisomeric lactones that could be separated by simple differential precipitation. Opening of these lactones with various nucleophiles efficiently led to a variety of novel C-glycosyl-α-hydroxy esters or amides that could be isolated by simple precipitation. The main advantages of these procedures include the use of unprotected sugars, the divergent entry they provide to a panel of novel C-glycosides that can be readily isolated by precipitation, their scalability, and their cost-effectiveness. Cosmetic applications of these novel Cglycosides will be further explored and reported.16
diastereoisomers, starting from 225 g of D-xylose 5b. A sequence of treatment with acidic resins helped to remove the majority of organic and inorganic salts (
