Stereoselective synthesis of substituted 1,2-annulated sugars by domino double-Michael addition reaction

Accepted Manuscript Stereoselective synthesis of substituted 1,2-annulated sugars by domino doubleMichael addition reaction Kadigachalam Parasuraman, Ande Chennaiah, Sateesh Dubbu, A.K. Ibrahim Sheriff, Yashwant D. Vankar PII:

S0008-6215(19)30080-1

DOI:

https://doi.org/10.1016/j.carres.2019.03.007

Reference:

CAR 7689

To appear in:

Carbohydrate Research

Received Date: 5 February 2019 Revised Date:

4 March 2019

Accepted Date: 18 March 2019

Please cite this article as: K. Parasuraman, A. Chennaiah, S. Dubbu, A.K. Ibrahim Sheriff, Y.D. Vankar, Stereoselective synthesis of substituted 1,2-annulated sugars by domino double-Michael addition reaction, Carbohydrate Research (2019), doi: https://doi.org/10.1016/j.carres.2019.03.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Stereoselective Synthesis of Substituted 1,2-Annulated Sugars by Domino Double-Michael Addition Reaction Kadigachalam Parasuraman,a,b Ande Chennaiah,a Sateesh Dubbu,a A. K. Ibrahim Sheriff,b Yashwant D. Vankara,* a

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Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, 208016, India PG and Research Department of Chemistry, C. Abdul Hakeem College (Autonomous), Melvisharam, 632509, Tamil Nadu, India

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Abstract

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A simple, highly stereoselective one-pot methodology for the synthesis of novel 1,2-annulated sugars comprising of oxa-oxa and oxa-carbasugar fused skeletons from 2-nitrogalactal and a sugar-derived enone, obtained from 2-formylgalactal, promoted by KOtBu and CH3ONa

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respectively is described. Both processes rely on a domino double-Michael addition reaction resulting in the formation of three stereocenters in a single pot, including a quaternary center.

Keywords: Domino Double-Michael Addition Reaction; 1,2-Annulated Sugars; 2-Nitrogalactal;

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Sugar-Derived Dienone.

1. Introduction

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Among the essential biomolecules of all living cells, carbohydrates have been recognized as a significant class of molecules,1 since they play an important role in several biological processes,

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such as cell–cell recognition,2a reproduction,2b and protein folding.2c One of the most important subfamilies of carbohydrates is 1,2-annulated sugars in which a sugar backbone is fused with a

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O-, N- or C-glycosyl unit at C-1 and C-2 positions.3 1,2-Annulated sugars have received an enormous attention as a result of their diverse structures and potent biological activities.4 For instance, sugar-fused benzopyran I (Figure 1) acts as a potent ligand for A amyloid peptides.5 Similarly, 1,2-annulated sugar II is an important synthon in the total synthesis of ansamycins.6 In this context, our group has reported7 synthesis of novel 1,2-annulated sugars III and IV, which were found to be selective glycosidase inhibitors. Therefore, for the past few years several methods have been developed4,8 towards the synthesis of 1,2-annulated sugars. Generally, glycals and their derivatives such as 2-nitroglycals, 2-haloglycals and glycal epoxides have been used as synthons for the synthesis of 1,2-annulated sugars.3a However, the reported methods

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require a relatively large number of synthetic steps for procuring 1,2-annulated sugars. Thus, developing improved methods for the synthesis of 1,2-annulated sugars would be of great

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interest for the preparation of large libraries of new potentially biologically active compounds.

Figure 1. Biologically important 1,2-annulated sugar scaffolds. Due to their ecological and economical advantages, one-pot reactions such as domino or cascade reactions are always in greater demand in comparison to traditional multistep synthesis.9 In this context, double-Michael addition reaction is one of the powerful domino reactions for the synthesis of complex natural products and polycyclic compounds.10As part of our continued

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efforts in functionalizing sugar derivatives for the synthesis of a variety of biologically important

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molecules, recently we reported a one-pot three-component protocol for the synthesis of 2-Cbranched O-glycosides from 2-nitroglycals by trapping nitronate ion intermediate with a suitable

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electrophile in an intermolecular fashion.11

Scheme 1. General strategy for the construction of 1,2-annulated sugars through double Michael addition reaction

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Our continued research interest have led us to develop new approaches for the synthesis of 1,2annulated sugars.12 Toward this endeavor, we planned to apply domino double-Michael addition reaction strategy on suitable sugar substrates to synthesize 1,2-annulated sugars. Thus, we anticipated that reaction of (i) 2-nitroglycal13 with Baylis–Hillman alcohols,14 which possess a

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sp2-hybridized electrophilic carbon center, for the Michael addition as well as a nucleophilic (-OH) group (ii) sugar-derived dienone with soft -dianions as Michael donors, may lead to the formation of 1,2-annulated sugars in an intramolecular manner via double Michael addition reaction in one-step (Scheme 1). Herein we report the realization of such a strategy for the

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synthesis of substituted 1,2-annulated sugars via domino double-Michael addition reaction in one-step.

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2. Results and discussion

To explore the feasibility of the proposed double-Michael addition strategy leading to 1,2annulated sugars, we began our study by performing a reaction between 2-nitrogalactal 1 and the Baylis–Hillman alcohol 2. In our initial attempt, we conducted the reaction of 2-nitrogalactal 1 with 1.5 equiv of Baylis–Hillman alcohol 2 along with 1.5 equiv of Et3N as a base in CH2Cl2. However, no desired product was formed (Table 1, entry 1), and under the same conditions,

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change of base to pyridine and DBU also failed to give the expected product 3 (Table 1, entries 2

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and 3). Thereafter, when we used 1.5 equiv of LiHMDS as a base in Et2O (Table 1, entry 4), it led to the formation of product 3 having the same Rf as that of the Baylis–Hillman alcohol 2 on thinlayer chromatography, which was separated by column chromatography with great difficulty in

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34% yield along with the recovered staring material. Further, increasing the amount of LiHMDS to 2 equiv and using THF as a solvent (Table 1, entry 5), we observed some improvement in the

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yield of the desired product 3. After exploring various combinations of bases and solvents (Table 1), it became clear that the use of 2 equiv of KOtBu in THF at 0 oC to room temperature was optimum to form product 3 in 75% yield in 8 h. The structure of this product 3 was established with the help of COSY and NOE experiments. Thus, in NOE experiments (Figure 2), irradiation of proton H-1 at  5.68 led to the enhancement of signal for H-7 at  5.06 but no enhancement was observed for H-3 and H-5 protons suggesting that H-1 and H-7 are -oriented. Further, appearance of H-7 as a doublet with coupling constant J = 8.24 Hz indicated that H-7 and H-8 are trans-dixially oriented.

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Table 1. Optimization of reaction conditions for the domino double Michael reaction.

Entry

Base

Equiv

Solvent

Time (h)

Yield (%)

1

Et3N

1.5

CH2Cl2

24

2

Pyridine

1.5

CH2Cl2

24

n.r.

3

DBU

1.5

CH2Cl2

24

n.r.

4

LiHMDS

1.5

5

LiHMDS

2.0

6

NaH

2.0

7

NaH

2.0

8

KOtBu

2.0

9

KOtBu

2.0

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n.r.

12

34a

THF

12

40 a

Et2O

8

45 a

THF

8

48

Et2O

10

53

THF

8

75

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Reaction conditions: 2-nitrogalactal 1 (0.22 mmol), BaylisHillman alcohol 2 (0.33 mmol), KOtBu (0.44 mmol), dry THF (4 mL), 0 °C to rt, N2 atmosphere, Isolated yields after purification by silica gel column chromatography, aYield based on recovered starting material; n.r. (not reacted)

Figure 2. NOE of compound 3.

Next, with a view to demonstrate a broader substrate scope of the present protocol, reaction was explored with various Baylis–Hillman alcohols derived from different aryl aldehydes and methyl

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the two enanatiomers may have reacted15 with the nitrosugar 1 leading to the observed products. We therefore subjected all the inseparable mixtures to selective reduction11 of the nitro group with Zn/HCl-CH3CO2H to the corresponding amine followed by acetylation to give the corresponding chromatographically separable 2-acetamido-1,2-annulated sugars 4-12 (Scheme

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2). The reaction appears quite general with respect to various Baylis–Hillman alcohols derived from different aryl aldehydes and methyl acrylate, providing the desired 2-acetamido-1,2-

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annulated sugars in moderate to good yields (Scheme 2). Thus, as shown in Scheme 2,

Scheme 2. Double Michael addition reaction of 2-nitrogalactal 1 with different Baylis–Hillman alcohols.

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several Baylis–Hillman alcohols bearing aryl groups having p-chloro (5), p-methyl (6), p-bromo (7), p-methoxy (8), m-fluoro (11) and m-bromo (12) substitution led to the desired 2-acetamido1,2-annulated sugars successfully. Interestingly, bulky group containing 1-naphthaldehyde derived Baylis–Hillman alcohol also participated in the reaction and afforded the corresponding

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product 10, albeit in 53% yield. The stereochemistry of newly generated stereocenters of 2acetamido-1,2-annulated sugars was proved by 1H and 13C NMR spectroscopy, including COSY and NOE, and found exclusively to be single diastereomers. Thus, in NOE studies of compound 5 (Figure 3), irradiation of the signal for H-1 at δ = 5.76 led to an enhancement of the H-7 peak

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at δ = 4.79 and no enhancement was observed for H-3 and H-5 protons suggesting that H-1 and H-7 are -oriented. Next, the stereochemistry of proton H-8 was assigned from the coupling

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constant of H-7 appearing at δ = 4.79 as a doublet with J = 10.52. This large J1,2 value indicates

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that H-7 and H-8 are trans-diaxially oriented.

Figure 3. NOE of compound 5.

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To demonstrate the utility, the ester functionality of one of the synthesized 1,2-annulated sugars was further exploited. Thus, the 1,2-annulated sugar 13 (as a mixture containing a small amount of the unreacted Baylis–Hillman alcohol) was subjected to selective reduction of the ester group

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with NaBH4 along with BF3∙OEt216 followed by acetylation of the resulting primary alcohol with Ac2O/Et3N to give the corresponding acetoxy derivative 14 in 73% overall yield in two steps (Scheme 3). On the other hand, compound 13 was subjected to saponification of the ester group by using NaOH in CH2Cl2/MeOH17 to afford the corresponding acid derivative 15 in 76% yield as a crystalline compound and its stereochemistry was confirmed by X-ray crystallographic analysis18 (Figure 4). Thus, it additionally supports the configurations of other synthesized 1,2annulated sugars (Scheme 2, 4-12) as confirmed by the spectral data.

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Scheme 3. Synthetic Transformations of compound 13.

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Figure 4. X- ray crystal structure of compound 15.

Based on the absolute configuration of the products, a plausible mechanism has been presented in Scheme 4. Thus, it is expected that the reaction proceeds via a typical Michael addition to form intermediate A from 2-nitrogalactal 119 and different Baylis–Hillman alcohols X in presence of KOtBu as a base. This is followed by an intramolecular Michael addition reaction on the ,-unsaturated ester moiety preferentially from the -side, due to the steric hindrance from

-side caused by the substituents at C-3, C-4 and C-5, to give intermediate B. The aryl group and the ester moiety prefer to occupy equatorial sides forming the observed 1,2-annulated sugars C.

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Scheme 4. Proposed mechanism for the double Michael addition reaction of 2-nitrogalactal 1

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with different Baylis–Hillman alcohols.

Having explored a stereoselective double-Michael addition reaction to access 2-acetamido-1,2annulated sugars from 2-nitrogalactal 1 and different Baylis–Hillman alcohols, we decided to

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explore the application of double-Michael addition reaction strategy on sugar-derived dienone 17 in the hope to form 1,2-annulated sugars having oxa-carbasugar fused skeletons in one-step

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(Scheme 1). Thus, the desired sugar-derived dienone 17 (Scheme 5) was readily synthesized from C2-formyl galactal20 16 by its reaction with commercially available vinylmagnesium bromide at 0 oC to room temperature in dry THF solvent. The resultant hydroxyl group was oxidized using IBX, giving sugar-derived dienone 17 in 63% yield over two steps (Scheme 5).

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Scheme 5. Synthesis of sugar-derived dienone 17.

After the synthesis of the desired sugar-derived dienone 17, initially, we chose acetylacetone as an active methylene pro-nucleophile to test the feasibility of the proposed double Michael

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reaction. Thus, dienone 17 was reacted with acetylacetone in the presence of KOtBu (2 equiv) as a base at 0 °C to room temperature, but to our disappointment we did not observe any reaction and the starting material was recovered. After exploring various combinations of the bases and solvents, it became clear that a combination of CH3ONa (2 equiv) as a base in CH3OH/THF (5:1) at 30 oC to room temperature was optimum to form the corresponding 1,2-annulated sugar 18 in

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75% yield in 2 h via double-Michael addition reaction strategy. Under the optimized conditions, scope of the double-Michael addition reaction with dienone 17 was evaluated, and the results are

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described in Scheme 6. A few active methylene pro-nucleophiles such as dibenzoylmethane, dimethyl malonate and cyclohexane-1,3-dione were reacted with the sugar-derived dienone 17

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and the corresponding 1,2-annulated sugars 19, 20 and 21 were obtained in good yields (Scheme 6). The present reaction was found to be highly stereoselective to give 1,2-annulated sugars 18-

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21 as single diastereomers and the stereochemistry of newly generated centers was confirmed by NMR studies. Thus, in the 1H NMR spectrum of 1,2-annulated sugar 18 the anomeric proton (H1) appeared as a doublet at  5.26 with J = 2.70 Hz. In the NOE experiments of compound 18, irradiation of the signal of H-1 at  5.26 did not lead to an enhancement of the H-3 and H-5 signals at 4.43 and  4.26 respectively. This implies that H-1 proton is trans to H-5 and H3 and thus axially oriented (Figure 5). The homonuclear decoupling of H-1 at = 5.26 resulted the proton H-2 to appear as a doublet from a triplet, with J = 3.20 Hz at  = 3.15 indicating that H-2 and H-3 are trans-diequatorially oriented.

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Scheme 6. Synthesis of 1,2-annulated sugars from sugar-derived dienone 17 via double Michael

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addition reaction.

Figure 5. NOE of compound 18.

A plausible reaction mechanism for the stereoselective formation of 1,2-annulated sugars 18-21 from sugar-derived dienone 17 is given in Scheme 7. Initially intermolecular Michael addition of active methylene pronucleophiles X to sugar-derived dienone 17 by CH3ONa may lead to the formation of intermediate A. This is then followed by formation of intermediate C through intermediate B via an intramolecular Michael addition reaction. Due to steric repulsion from the

ACCEPTED MANUSCRIPT three –OBn groups at C3, C4 and C5 positions from-face, formation of intermediate C preferentially takes place from -face to afford the corresponding 1,2-annulated sugars 18-21

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(Scheme 7).

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3. Conclusion

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Scheme 7. A plausible reaction mechanism for the formation of 1,2-annulated sugars 18-21.

In conclusion, we have shown the utility of domino double-Michael addition reaction between 2-

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nitrogalactal and different aryl substituted Baylis–Hillman alcohols, and a sugar-derived dienone with active methylene pronucleophiles to the construction of 1,2-annulated sugars having oxa-

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oxa and oxa-carbasugar fused skeletons respectively. Remarkable advantages of these new strategies include high stereoselectivity, mild reaction conditions and can be used for the synthesis of novel 1,2-annulated sugars with multiple stereocenters.

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4. Experimental section 4.1 General procedure ‘A’ for the domino double Michael addition reaction of 2nitrogalactal 1:

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To a stirred solution of 2-nitrogalactal 1 (100 mg, 0.22 mmol, 1.0 equiv), and a Baylis-Hillman alcohol (1.5 equiv) in dry THF (5 mL), at 0 oC was added potassium t-butoxide (2 equiv) portion wise over 5 min under N2 atmosphere. The reaction mixture was brought to room temperature, and allowed to stir for 8 h. After consumption of 2-nitrogalactal 1 (TLC monitoring) the reaction mixture was quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with ethyl

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acetate (3 × 10 mL). The combined organic extracts were washed with water (1 × 5 mL), brine solution (1 × 5 mL) and dried over anhydrous Na2SO4. The solvent was evaporated to give the

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crude product. To a stirred solution of this crude compound (100 mg) in THF (5 mL), was added concentrated HCl (0.5 mL), acetic acid and water (7 mL, 1:2). The reaction mixture was cooled to 0 0C and Zn dust (20 equiv) was added in portions. After stirring for 3 h at this temperature, the cooled residue was filtered and the filtrate was then extracted with dichloromethane (3 × 15 mL). The combined organic extracts were washed with water (1 × 5 mL), saturated aqueous NaHCO3 solution (1 × 5 mL) and dried over anhydrous Na2SO4. The solvent was evaporated in

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vacuo to give the crude amine which was then subjected to N-acetylation. Thus, the crude amine

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(100 mg, 0.16 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL) under N2 atmosphere and treated with Et3N (2.0 equiv), acetic anhydride (2.0 equiv) and DMAP (10 mol%) at 0 oC.

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The reaction mixture was allowed to stir for 2 h at room temperature. After completion of reaction (TLC monitoring) the reaction mixture was quenched by adding aqueous saturated NaHCO3 solution (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic extracts were

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washed with brine solution (1 × 5 mL) and dried over anhydrous Na2SO4. The solvent was evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography using hexane and ethyl acetate as eluents to afford the corresponding 2acetamido-1,2-annulated sugars (Scheme 2).

ACCEPTED MANUSCRIPT 4.2 General procedure ‘B’ for the domino double Michael addition reaction of sugarderived dienone 17: To a stirred solution of an active methylene pronucleophile (1.2 equiv) in freshly prepared dry methanol (3 mL) was added CH3ONa (2 equiv) at -30 oC under N2 atmosphere followed by

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sugar-derived dienone 17 (125 mg, 0.27 mmol, 1 equiv) dissolved in CH3OH/THF (5:1, 2 mL). The reaction mixture was slowly brought to room temperature and continued to stir for appropriate time (Scheme 6). After consumption of starting material (TLC monitoring), the reaction mixture was quenched with saturated NH4Cl solution (5 mL) and extracted with ethyl

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acetate (3 × 10 mL). The combined organic extracts were washed with water (1 × 5 mL), brine solution (1 × 5 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under

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reduced pressure and the crude compound was purified by silica gel column chromatography with ethyl acetate and hexane mixtures to afford the pure product (Scheme 6).

Acknowledgment

We are grateful to the Department of Science and Technology, New Delhi, India, for a J. C. Bose National Fellowship to YDV (Grant No. JCB/SR/S2/JCB-26/2010). KP expresses sincere thanks

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to Prof. Y. D. Vankar, IIT Kanpur for allowing to use all the facilities in his laboratory. AC and

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SD thank the Council of Scientific Industrial Research, New Delhi for Senior Research

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Baylis-Hillman alcohols were isolated as their acetates after acetylating the crude reaction mixtures. The detailed experimental procedure is given in the Supporting Information. This clearly indicates that only one of the two enantiomers of the Baylis-Hillman alcohols reacts. Based on the structures assigned to the 3-12, the absolute configurations of the two

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[18] See the Supporting Information. CCDC number of compound 15: 1559979. [19] Attempts to use benzyl protected 2-nitroglucal and 2-formylglucal did not lead to clean reactions. Hence we have carried out reactions with only galactal derivatives.

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Domino double-Michael addition reaction was explored in carbohydrate chemistry for the synthesis of novel 1,2-annulated sugars 2-nitrogalactal and C2-formyl galactal derived dienone were used as a synthons

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1,2-annulated sugars with oxa-oxa as well as oxa-carbasugar skeletons were prepared

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