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Synlett 2010(14): 2174-2178  
DOI: 10.1055/s-0030-1258498
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solvent-Free and Stereoselective Synthesis of C-Glycosides by Michael-Type Addition of Enamino Esters to 2-Nitro-d-glucal

Ti Zhanga,b, Chu-Yi Yu*a, Zhi-Tang Huang*a, Yue-Mei Jiaa
a Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax: +86(10)82616433; e-Mail: yucy@iccas.ac.cn;
b Graduate University of Chinese Academy of Sciences, Beijing 100049, P. R. of China

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Publication History

Received 13 April 2010
Publication Date:
16 July 2010 (online)

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Abstract

Michael-type addition of enamino esters to 3,4,6-tri-O-benzyl-2-nitro-d-glucal under solvent-free conditions formed C-glycosides in excellent yields with high stereoselectivity. Reduction of the nitro group afforded the corresponding bicyclic 2-amino C-glycosides.

Key words

solvent-free - C-glycosides - Michael-type addition

C-Glycosides, either synthetic or naturally occurring, are an important class of bioactive compounds. [¹] In contrast to their O-analogues, C-glycosides are less vulnerable to enzymatic and chemical hydrolyses, which has led to significant interest in their viability as drug candidates and enzyme inhibitors. The synthesis of C-glycosides has hence attracted much attention from synthetic organic chemists and methods for the formation of C-glycosides are well documented in the literature. [²] The synthetic strategy for C-glycosides usually involves the construction of the anomeric C-C bond using the nucleophilic, electrophilic, or radical character of the anomeric center, and concerted reactions have also been employed for C-glycosidation. [³] Electrophilic reactions were probably most widely applied to C-glycosidation and commonly used C-nucleophiles include organometallics, cyanides, C-silylate compounds, alkenes, and activated aromatic and β-dicarbonyl compounds. Only a few applications of enamino esters as nucleophiles for C-glycosidation have been reported in the literature. [4] Due to their easy preparation, considerable stability, and bisnucleophility, enamino esters are a remarkable class of synthetic intermediates with diverse reactive properties, and they have been widely used in the synthesis of alicyclic, aromatic and heterocyclic compounds. [5] Hence, it would be significant not only in carbohydrate chemistry but also in synthetic organic chemistry to develop a convenient, efficient and practical method for the C-glycosidation of enamino esters.

Solvent-free reactions, due to the advantages of less pollution, lower expense, and easier procedures, have attracted considerable attention from synthetic organic chemists. [6] However, the application of solvent-free reactions in carbohydrate chemistry has been limited. [7] Herein, we report a solvent-free C-glycosidation method by using Michael-type addition of enamino esters to 3,4,6-tri-O-benzyl-2-nitro-d-glucal (1). [8]

Scheme 1 Solvent-free and stereoselective C-glycosidation by Michael-type addition of enamino esters to 2-nitro-d-glucal

The 2-nitro-d-glucal 1 was prepared according to a reported method. [9] Enamino ester 2d was chosen as a model substrate in the test reactions with 1 (Scheme  [¹] ; R¹ = Ph, R² = Bn). Considering that the Michael addition reactions were usually performed with the aid of a base, [¹0] the reactions between 1 and 2d were initially carried out in the presence of various bases, such as: NaH, t-BuOK, CH3ONa, DBU, Et3N or DMAP, and in various solvents (CH2Cl2, MeCN, THF, 1,4-dioxane, toluene or DMF). Unfortunately, either no reaction occurred or complex mixtures of products were generated under such reaction conditions. Subsequently, in order to optimize the reaction conditions, the influence of concentration on the outcome of the glycosidation was examined, and the reaction between 1 and 2d was attempted in concentrations ranging from 0.05 M to solvent-free conditions. To our delight, the reaction proceeded smoothly to give C-glycoside 3d under solvent-free conditions. The appropriate temperature for the reaction, in terms both of yield and reaction time, was found to be 110 ˚C. [¹¹] The reaction between a variety of enamino esters [¹²] 2a-k and 1 were then attempted (Table  [¹] ). All reactions were complete within 5-8 hours and resulted in the formation of the desired C-glycosides 3a-k in good yield (85-94%) with excellent β-stereoselectivity. The reactions of the enamino esters derived from ethyl acetoacetate (2i-k) with 1 should be performed at temperatures below 95 ˚C (Table  [¹] , entries 9, 10, and 11) to avoid low yields. Although both β-C- and N-positions of enamino esters can act as nucleophilic centers and either could, in principle, be involved in the reactions with 1, no N-glycoside was detected. Therefore, the reactions between 1 and 2 proceeded smoothly with excellent regio- and stereoselectivity. The presence of a nitro group at C-2 seemed to allow anchimeric assistance and consequently orientated the glycosylation in the direction of the β-anomer.

Table 1 Michael-Type Addition of Enamino Esters to 2-Nitro-d-glucal

Entry Enamino ester R¹ R² Temp (˚C) Time (h) Yield (%)a
 1 2a Ph H 110 8 85
 2 2b Ph Me 110 6 87
 3 2c Ph Ph 110 5 90
 4 2d Ph Bn 110 5 94
 5 2e Ph n-Pr 110 7 88
 6 2f Ph i-Pr 110 5 92
 7 2g Ph CH2CH=CH2 110 8 92
 8 2h Ph CH2CO2Et 110 8 91
 9 2i Me H  95 6 91
10 2j Me CH2CH=CH2  95 5 93
11 2k Me Bn  95 3 94
a Combined isolated yields after column chromatography.

The configurations of C-glycosides were determined on the basis of their spectroscopic properties. For example, in the ¹H NMR spectra of 3d, the anomeric hydrogen signal appeared as a doublet with J 1 ′ ,2 ′ = 9.7 Hz. Similarly, the H-2′ signal appeared as a triplet with J 1 = J 2 = 9.7 Hz. This clearly indicated a trans relationship between H-1′ and H-2′, and between H-2′ and H-3′. The structure assignment was also supported by an NOE experiment that indicated strong interactions between H-1′ and H-3′/H-5′ and between H-2′ and H-4′. It was inferred that H-1′ and H-3′/H-5′ were on the same side, whereas H-2′ and H-4′ were on the other side. The X-ray single crystal analyses of 3d (Figure  [¹] ) and 3i (Figure  [²] ) unambiguously confirmed these assignments. [¹³]

Figure 1 X-ray crystal structure of 3d; partial hydrogen atoms bonded to carbon atoms have been omitted for clarity. The intramolecular hydrogen bond is indicated by a dashed line.

Figure 2 X-ray crystal structure of 3i; partial hydrogen atoms bonded to carbon atoms have been omitted for clarity. The intramolecular hydrogen bond is indicated by a dashed line.

Subsequently, we focused our attention on the C-glycosidation of heterocyclic enamines 4 (Table  [²] ). The solvent-free reactions of heterocyclic enamino esters 4a and 4b [¹4] were conducted at 85 ˚C and were complete within 30 minutes, whereas the reactions of nitro-substituted heterocyclic enamines 4c and 4d [¹5] required longer reaction times and did not go to completion. The conversion ratio was not improved by addition of a base; on the contrary, the yields decreased dramatically (20-25%), due to the decomposition of 2-nitroglucal 1. C-Glycosidation of heterocyclic enamino esters could proceed when refluxing in MeCN, albeit in lower yields. Because 2-nitroglucal 1 did not react completely (Table  [²] , entries 2 and 5), a catalytic amount of Et3N was added to solve this problem (Table  [²] , entries 3 and 6). For six-membered heterocyclic enamines, only the β-anomer was obtained, whereas five-membered enamines afforded a mixture of two anomers. The results indicated that compounds with six-membered rings showed better stereoselectivity than those with five-membered rings.

The configurations of the C-glycosides were determined by analysis of their ¹H NMR and NOE spectra. For the α-anomer, the H-1′ signal appeared as a doublet with J 1 ′ ,2 ′ = 9.8 Hz, indicating a trans arrangement for H-1′ and H-2′; while the H-2′ signal appeared as a double doublet with J 2 ′ ,3 ′ = 3.7 Hz, indicating axial/equatorial arrangement for H-2′ and H-3′ and a ¹ C 4 conformation for 5a-. This structural assignment was also supported by an NOE experiment, which demonstrated a strong interaction between H-1′ and H-6′.

Table 2 Michael-Type Addition of Heterocyclic Enamines to 2-Nitro-d-glucal

Entry 4 n, R³ Solvent Temp (˚C) Additive Recovered 1 (%) Time (h) Yield (%) β/α
1 4a 0, CO2Et - 85 - - 0.5 96a 98:2b
2 4a 0, CO2Et MeCN reflux - 10 5 74a 90:10b
3 4a 0, CO2Et MeCN reflux Et3N - 5 89a 90:10b
4 4b 1, CO2Et - 85 - - 0.5 94  1:0
5 4b 1, CO2Et MeCN reflux - 15 8 70  1:0
6 4b 1, CO2Et MeCN reflux Et3N - 8 84  1:0
7 4c 0, NO2 - 85 -  7 4 86a 93:7c
8 4d 1, NO2 - 85 -  9 6 79  1:0
a Combined isolated yield after column chromatography.
b Ratio was determined from the isolated pure diastereomers.
c Ratio was determined by integration of the H-2′ signal in the ¹H NMR spectra (300 MHz).

The presence of a nitro group at C-2′ has several advantages; in particular, it would provide access to various 2-amino-C-glycosides, [¹6] which are important components of many glycoproteins that are attractive targets for the design of C-linked carbohydrate mimetics. [¹7] Accordingly, we then attempted the reduction of the nitro group. A variety of reagents and conditions for reduction of the nitro groups [¹8] were screened, including Raney Ni, Zn/Ac2O and Zn/AcOH, but all these conditions led to unidentifiable mixtures of products. Fortunately, reduction of compound 3 with four equivalents of zinc dust and four equivalents of NH4Cl in ethanol proved to be a relatively clean reaction, resulting in the formation of the unexpected bicyclic compounds 6 and 7 in good yields. Bicyclic compounds 6 and 7 were clearly formed through a sequence of reactions, i.e., reduction of the nitro group, followed by subsequent intramolecular cyclization along with the elimination of the amino group of the aglycon.

Table 3 Reduction of 2-Nitro-C-glycosides

Entry 2-Nitro-C-glycoside R² Time (h) Yield (%)a Ratio 6/7 b
1 3a H 0.5 82 1.2:1
2 3d Bn 0.5 87 3:1
3 3e n-Pr 0.5 83 1.6:1
4 3h CH2CO2Et 0.5 85 2:1
a Combined isolated yield after column chromatography.
b The ratio of 6 and 7 was determined by the isolation of pure diastereomers.

The ratio of products 6 and 7 ranged between 3:1 to 1.2:1 (Table  [³] ); the configurations of the products were determined by ¹H NMR and NOE experiments. For compound 6, the H-3 signal appeared at δ = 3.18 ppm as a double doublet with J 1 = 9.8 Hz and J 2 = 8.2 Hz, and the H-7a signal appeared at δ = 3.32 ppm as a triplet with J 1 = J 2 = 9.2 Hz. NOE experiments showed interactions between H-3a and H-2/H-5/H-7 and between H-7a and H-3/H-6, which indicated a trans relationship between H-2/H-3, H-3/H-3a and H-3a/H-7a. The H-3 signal of compound 7 appeared at δ = 2.91 ppm as a double doublet with J 3,2 = 8.9 Hz and J 3,3a = 3.0 Hz, and the H-7a signal appeared at δ = 3.24 ppm as a triplet with J 1 = J 2 = 9.2 Hz. The trans relationship between H-2/H-3 and H-7a/H-3a and the cis relationship between H-3/H-3a could be observed from an NOE experiment (Figure  [³] ).

Figure 3 Key NOE correlations for bicyclic compounds 6 and 7

In conclusion, an efficient, solvent-free C-glycosidation method has been developed based on the Michael-type addition of enamino esters to 3,4,6-tri-O-benzyl-2-nitro-d-glucal, which results in the formation of the desired C-glycosides in good yields and with excellent regio- and stereoselectivity. Reduction of the nitro group gave access to novel bicyclic 2-amino C-glycosides that are potentially useful as bioactive compounds, such as inhibitors of glycosidases.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

This work is supported by The National Natural Science Foundation of China (No. 20472086), The National Basic Research Program of China (No. 2009CB526511), The Ministry of Science and Technology and the Ministry of Health of the P. R. of China (No. 2009ZX09501-006), and The Chinese Academy of Sciences.

11

General experimental procedure: A mixture of 2-nitro-d-glucal 1 (1.0 mmol) and enamino ester 2 (1.2 mmol) was heated to the specified temperature in a silicone oil bath, as indicated in Table 1. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and purified by column chromatography using a mixture of ethyl acetate and petroleum ether as the eluent to furnish the target product.

13

The crystal structures of 3d and 3i have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition numbers CCDC 778452 and 778453, respectively.

11

General experimental procedure: A mixture of 2-nitro-d-glucal 1 (1.0 mmol) and enamino ester 2 (1.2 mmol) was heated to the specified temperature in a silicone oil bath, as indicated in Table 1. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and purified by column chromatography using a mixture of ethyl acetate and petroleum ether as the eluent to furnish the target product.

13

The crystal structures of 3d and 3i have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition numbers CCDC 778452 and 778453, respectively.

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Scheme 1 Solvent-free and stereoselective C-glycosidation by Michael-type addition of enamino esters to 2-nitro-d-glucal

Figure 1 X-ray crystal structure of 3d; partial hydrogen atoms bonded to carbon atoms have been omitted for clarity. The intramolecular hydrogen bond is indicated by a dashed line.

Figure 2 X-ray crystal structure of 3i; partial hydrogen atoms bonded to carbon atoms have been omitted for clarity. The intramolecular hydrogen bond is indicated by a dashed line.

Figure 3 Key NOE correlations for bicyclic compounds 6 and 7