Letter Cite This: Org. Lett. 2018, 20, 5186−5189
pubs.acs.org/OrgLett
Glycosylation of a Ketone with an O‑Glycosyl Trichloroacetimidate Provides an Enol Glycoside Xianglai Liu,†,§,⊥ Sumei Ren,§,⊥ Qi Gao,‡ Chun Hu,*,† Yingxia Li,§ and Ning Ding*,§,∥ †
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Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China ‡ China State Institute of Pharmaceutical Industry, Shanghai 201203, China § School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China ∥ Zhangjiang Technology Institute, Fudan University, 825 Zhangheng Road, Shanghai 201203, China S Supporting Information *
ABSTRACT: An enol-type glycosylation reaction has been investigated. Enol glycosides can be obtained from the reaction between O-glycosyl trichloroacetimidates and the corresponding ketones promoted by an acid. The enol glycosides derived from cyclic ketones can be afforded efficiently and isolated in good yield, while those from acyclic ketones are prepared in low conversion or are too labile for isolation. Further studies on different glycosyl donor types indicate that only the O-glycosyl trichloroacetimidate works well as a donor for enol glycosylation.
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the reported methods only provide acyclic enol glycosides, with the synthesis of cyclic enol glycosides not being well studied. Cyclic enol glycosides could be very useful for designing acid-sensitive, glycosidase-sensitive chemical probes or prodrugs12−14 and are potentially useful in the synthesis of C-glycoside by the O-to-C rearrangement.3,15,16 To the best of our knowledge, direct glycosylation of a ketone to form an enol glycoside has only been reported by the Saita group, who incidentally found17 that an α,β-unsaturated ketone on a glycyrrhetinate scaffold was subject to glycosylation with per-acetylated D-glucopyranosyl bromide under the typical Koenigs−Knorr reaction conditions to afford an enol glycoside. However, this method could only be applied to an α,β-unsaturated ketone rather than a regular ketone, and the substrate scope has been limited to several triterpenes and steroids.18 In addition, the Koenigs−Knorr reaction conditions involved in the above cases also are not satisfactory. In this regard, stoichiometric amounts of heavy metal salts are used as activators/promoters, and sometimes hazardous and even explosive solvents are needed.18
umerous methods have been developed for the formation of the O-glycosidic linkages since the first chemical glycosylation reaction was reported by Michael in 1879.1 The construction of O-glycosidic linkages is usually achieved by the reaction between a glycosyl donor and glycosyl acceptor (OH or COOH) in the presence of an activator or promoter.2 Most O-glycoside formations follow general strategies. However, in certain special cases, such as enol Oglycosidic linkages, their formation often requires special synthetic approaches. For example, some acyclic enol glycosides, as represented by the O-isopropenyl and O-butenyl glycosides, are usually derived from corresponding allyl-type glycosides through isomerization, and these have been used extensively as glycosyl donors in oligosaccharide synthesis.3−6 Other methods for their formation include conversion of the 1O-formyl glycosides into the corresponding 1-O-vinyl glycosides by Tebbe olefination,7 or adding the C(1)−OH of a glycosyl hemiacetal to ethyl phenyl propiolate in the presence of a strong base,8 or palladium-catalyzed vinylation of a protected monosaccharide bearing a free C(1)−OH,9 etc.3,10,11 The current methods for acyclic enol glycosylation require a careful selection of techniques, their modification, or the design of conceptually new approaches.2 Moreover, most of © 2018 American Chemical Society
Received: July 6, 2018 Published: August 24, 2018 5186
DOI: 10.1021/acs.orglett.8b02126 Org. Lett. 2018, 20, 5186−5189
Letter
Organic Letters In the course of our synthetic studies on glycoprobes,19−21 we became involved in the synthesis of enol glycosides. Here, we now report our recent work on the direct glycosylation of a ketone with an O-glycosyl trichloroacetimidate under typical glycosylation conditions. This method is mild, general, and efficient for the synthesis of a wide scope of enol glycosides, especially cyclic enol glycosides. Initially we examined the glycosylations of 2,3,4,6-tetra-Obenzoyl-D-galactopyranosyl trichloroacetimidate (D1) and 2indanone (A1) in DCM (dichloromethane) in the presence of a series of acids (Table 1, entries 1−8). The results indicate
not occur at all in CH3CN, THF, or 1,4-dioxane (entries 10− 12). We speculate that these heteroatom-containing solvents compete with ketones for TMS or proton electrophiles, which therefore hamper the acid-induced keto−enol tautomerism. In turn, the glycosylation would not happen. After this preliminary reaction screening, the relatively more appropriate conditions (described in Table 1, entry 3) were selected for subsequent investigations to explore the scope of the substrates. As shown in Scheme 1, different cyclic ketones have been selected and glycosylated. The glycosylations of 5 to 12
Table 1. Glycosylation Condition Investigationsa
Scheme 1. Glycosylation of O-Glycosyl Trichloroacetimidates with Cyclic Ketonesa
a All yields are isolated yields of the isomer mixtures. α/β ratio is determined based on the 1H NMR spectra of the isomer mixtures.
that 10 mol % of TfOH, TBSOTf, or TMSOTf is sufficient to bring about the glycosylation to provide the corresponding enol glycoside (G1) with similar anomeric selectivity outcomes (entries 1−3). In contrast, 100 mol % of SnCl4 or BF3·Et2O is not able to promote this reaction to form the enol glycoside, and a slight amount of the disaccharide B1 is isolated along with hydrolyzed donor (entries 4 and 5). It is noteworthy that the α/β ratio of the formed glycosidic bond is affected by the amount of TMSOTf and the reaction temperature. Thus, product G1 is obtained with an α/β ratio ranging from 2.3:1 (10 mol % of TMSOTf, entry 3) to α-only (100 mol % of TMSOTf, entry 6). Presumably, an acidcatalyzed β-glycoside to α isomerization is accelerated with an increase of acid.2,6 This speculation is supported by the following experiment. When the isolated β-G1 was treated with TMSOTf (mol 100%) in DCM for 1 h at 0 °C, it transformed into the thermodynamic product α-G1 (60%) exclusively along with some hydrolyzed sugar (32%). On the other hand, when the glycosylation was carried out at −78 °C, the β-glycoside prodominated (entry 8), presumably because of kinetic control of the reaction, downshift of the acid-catalyzed β to α isomerization, or the mixed effect. Solvent effects were also investigated. Among a variety of solvents, DCM was the most suitable, as was toluene which worked as well as DCM. It is interesting that glycosylation did
All yields are isolated yields. α/β ratio was determined based on the H NMR spectra.
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1
carbon-membered monocyclic ketones with D1 afford the corresponding enol glycosides (G2−G6) expeditiously. To explore the scope of the glycosyl donors, 2-indanone (A1) was selected to react with the trichloroacetimidate of D glucopyranosyl (D2), D-mannopyranosyl (D3), D-ribofuranosyl (D4), D-xylopyranosyl (D5), L-arabinopyranosyl (D6), or maltosyl (D7) donors, providing the corresponding enol 5187
DOI: 10.1021/acs.orglett.8b02126 Org. Lett. 2018, 20, 5186−5189
Letter
Organic Letters
Scheme 3. Glycosylation of O-Glycosyl Trichloroacetimidates with Triterpenes and Steroidsa
glycosides (G7−G12, respectively) smoothly. Additionally, other fused cyclic ketones, such as 1-indanone, 2-tetralone, and 7-methoxy-4-chromanone worked as well as A1 to provide G13−G15, respectively. Unfortunately, G15 was too labile for isolation, although the TLC (thin-layer chromatography) and LC-MS analysis showed a high conversion of the ketone to G15. To our delight, two substituted naturally occurring monocyclic ketones, methyl dihydrojasmonate and (−)-menthone, both reacted efficiently with D3 to generate the corresponding products, G16 and G17, in decent yields. Removal of the benzoyls from these enol glycosides by using the Zemplén protocol was smoothly accomplished as represented by the deprotection of G3 and G14. We next attempted acyclic ketone glycosylation using a similar reaction process (Scheme 2). In the cases when isolated Scheme 2. Glycosylation of O-Glycosyl Trichloroacetimidates with Acyclic Ketones
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Donor (1 equiv) and acceptor (3 equiv) were dissolved in dry DCM at 0 °C, and then TMSOTf (0.1 equiv) was added into the mixture. The reaction mixture was stirred at 0 °C for 1 h before quenched.
drosterone was then employed as the acceptor to demonstrate the power of this enol glycoside formation on a steroid, which gave G30 in a yield of 86%. Deprotections of these triterpenes are also efficient. For example, G27 and G28 were converted to DP-27 and DP-28, respectively, in high yield. In order to know if the O-glycosyl trichloroacetimidate plays a key role in the enol glycoside formation or not, the most widely used glycosyl donors, namely, a glycosyl bromide, a thioglycoside, and an ortho-alkynylbenzoate, were employed to react with epiandrosterone (Table 2). First, when 2.5 equiv of D3 reacted with epiandrosterone in the presence of 10 mol % of TMSOTf, both G31 (63%) and G32 (23%) were formed (entry 1). Interestingly, when 80 mol % of TMSOTf was applied, the only product was the monoglycoylated one G31, despite a huge excess of donor D3 (4 equiv) (entry 2). We believe that the increased concentration of acid induced the decomposition of the enol glycoside of G32. The glycosyl bromide D817 could only react with the 3-OH rather than the 17-keto group (entry 3). Interestingly, the same thing happened with thioglycoside (D9),20 which only afforded G31 in 83% yield under its typical glycosylation conditions, in spite of the presence of the acid (entry 4). Not unexpectedly, the Yu’s donor ortho-alkynylbenzoate (D10),22 which is activated via a gold(I) catalyst, only provided the monoglycosylated product G31 (93%) as well, due to the avoidance of strong acids22 (entry 5). However, it is interesting that even though an extra 10 mol % of TMSOTf was added to the above reaction the ketone glycosylation was still not detected (entry 6). In conclusion, the glycosylation of an O-glycosyl trichloroacetimidate with a ketone catalyzed by an acid provides the corresponding enol glycoside expeditiously. Most of the newly formed enol glycosides that were derived from cyclic ketones are stable enough and can be isolated in high yield. We believe that this method of enol glycoside formation will be very useful
ketones served as the acceptors, for example, acetone, 3pentanone, 4-methoxyphenylacetone, acetoacetic ester, and acetylacetone, the reaction conversions were much lower than those of cyclic ketones (G18−G21). In the case of 4′methylacetophenone, TLC analysis clearly showed the quick disappearance of the donor along with formation of the expected glycoside upon the addition of the catalysts (confirmed by LC-ESIMS). However, the newly formed acyclic enol glycosides (see G22) were quite labile, most decomposing during standard workup (in the presence of Et3N) and silica gel chromatography (neutralized by Et3N). Aldehydes were also tried, but the reactions were messy (see G23). With the above information in hand, we extended our glycosylation to certain naturally occurring bioactive triterpenes and steroids. Methyl 3-oxo-olean-12-en-28-oate bearing a 3-ketone reacted with trichloroacetimidates D2, D4, and D7, providing the enol glycosides G24 (89%), G25 (66%), and G26 (89%), respectively (Scheme 3). Another triterpene bearing a 3-ketone, methyl 3-oxo-urs-12-en-28-oicate worked with D1 as well to furnish G27 (87%). Methyl 3,11-dioxo-30norolean-12-en-30-oate, which bears an isolated carbonyl at the 3-postion and an α,β-unsaturated ketone at the 11position, was employed as the acceptor to be glycosylated with D2. The results show that only the isolated carbonyl rather than the α,β-unsaturated ketone could form the corresponding enol glycoside G28 (87%). The successful synthesis of G29 (68%) indicated that the 6-keto group on a triterpene also serves as a good glycosyl acceptor. 3-O-Acetyl dehydroepian5188
DOI: 10.1021/acs.orglett.8b02126 Org. Lett. 2018, 20, 5186−5189
Letter
Organic Letters Notes
Table 2. Comparison of Glycosyl Donors with Different Leaving Groups
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Major Scientific and Technological Special Project of China for “Significant New Drugs Development” (2018ZX09711002-006-008) to N.D., the Shanghai talent development fund (2017) to D.N., and the Shanghai Science and Technology Committee (STCSM) for “Pujiang Talent Program (2017) 16PJ1432700” to Q.G.
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in the field of designing acid-sensitive, glycosidase-sensitive chemical probes or prodrugs.
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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.8b02126. Experimental procedures and NMR spectra for the synthesis of all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*C. H.: E-mail:
[email protected]. *N. D.: E-mail:
[email protected]. ORCID
Yingxia Li: 0000-0001-6782-8740 Ning Ding: 0000-0002-6797-8797 Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Author Contributions ⊥
X.L. and S.R. contributed equally. 5189
DOI: 10.1021/acs.orglett.8b02126 Org. Lett. 2018, 20, 5186−5189
