Base mediated green synthesis of enantiopure 2-C-spiro-glycosyl-3-nitrochromenes

Abstract

A novel green synthetic methodology has been developed to obtain enantiopure (2S)-2-C-spiro-glycosyl-3-nitrochromenes following the oxa-Michael–aldol condensation reaction of sugar derived 3-C-vinyl nitro olefins with substituted salicylaldehydes using Et₃N as a base under neat conditions at rt–40 °C. The stereochemistry of the product is confirmed by a single crystal X-ray study. Several advantages are associated with this protocol such as cost effectiveness, easy accessibility, short reaction time, high yields, wide substrate scope and high enantiopurity.

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Introduction

C-Glycosides represent an important class of bioactive compounds that are resistant to metabolic processing.¹ They play a pivotal role in developing novel materials, surfactants and bioactive molecules.² A broad class of natural products such as flavones,³ xanthones,⁴ chromenes⁵ and anthrones⁶ possess aryl-C-glycosides. The synthetic and natural products containing aryl-C-glycosides such as nothofagin, aspalathin, vitexin, papulacandin, tofogliflozin etc. are of great significance in medicinal chemistry owing to their stability toward enzymatic and chemical hydrolysis as compared to the O-glycosides (Fig. 1).⁷ These compounds possess a wide range of biological properties such as antioxidant, antidiabetic, potent enzyme inhibitor and anticancer properties.^3–6,8

Fig. 1 Selected bioactive aryl-C-glycosides and nitrochromenes.

Similarly, imparting stereochemistry in the quaternary centers of a carbohydrate building block for the generation of structurally intriguing and biologically potent natural products and building blocks is a daunting challenge in asymmetric synthesis and has attracted considerable attention in recent years due to their potential biological activities.⁹ Stereoselective formation of an oxa-quaternary carbon center at the anomeric position has been reported by various methods such as the semipinacol rearrangement reaction, intramolecular C–H insertion reaction, ring closing metathesis, palladium catalysed cross coupling reaction, 1,3-dipolar cycloaddition reaction, hetero-Michael addition reaction etc.¹⁰ The literature survey reveals a number of methods on the synthesis of analogues of natural spironucleoside (+)-hydantocidin, (−)-cinatrin B and papulacandin in which the heterocyclic ring was fused at the anomeric position.¹¹ But the stereoselective synthesis of six- or seven-membered C-spiro-heterocycles at the 3-position of glucofuranose has not been investigated extensively although the six-membered heterocyclic ring exists in many drug molecules as the core substructure and their derivatives are of very important biological significance.¹²

Similarly, chromenes and their derivatives belong to an important family of heterocycles that are widespread in plants¹³ and possess a broad range of biological properties.¹⁴ The current literature report reveals that 2H-chromenes and their derivatives such as S14161 and BENC-511 show potent anticancer activities (Fig. 1).^15,16 A key aspect is that the lipophilic nature of the benzopyran derivatives helps to cross the cell membrane more easily. Particularly, 3-nitro-2H-chromenes are of great importance because of their potential uses as pesticides, endothelin-A (ETA)-selective receptor antagonists, inhibitors of the proliferation of cancer cells, highly potent antihypertensive drugs, important intermediates (flavanol, chroman-3-amine) in the synthesis of medicinally active 2H-benzopyrans and potential candidates for nonlinear optical applications (Fig 1).^17–20 Due to the advent of simple methods of synthesis and high reactivity of 3-nitro-2H-chromenes, they are used as precursors for the synthesis of various complex natural products.²¹

On account of the biological significance of both C-spiro glycosides and nitrochromenes and due to our enormous interest towards the synthesis of spiro-C-glycosides, we became interested to fuse both of them in a single molecular framework to synthesize 2-C-spiro-glycosyl-3-nitrochromenes.

Herein we first report the enantiopure synthesis of 2-C-spiro-glycosyl-3-nitrochromenes in a fewer number of steps with good to excellent yields at rt–40 °C in a very short period of time under neat conditions. Moreover, the present discovery will also provide access for further functional group interconversion to increase the molecular complexity.

Though the syntheses of enantiopure 2-C-glycosyl-3-nitrochromenes were reported by Raquel G. Soengas et al.²² in multiple steps with moderate yield, enantiopure synthesis of 2-C-spiro-glycosyl-3-nitrochromenes has not been reported yet.

To the best of our knowledge, this is the first report on the development of a general methodology for the enantiopure construction of sugar fused nitrochromene derivatives, which are new types of C-spiro-glycosides.

Our synthetic endeavour commenced from commercially available salicylaldehydes 1 and 3-C-vinyl sugar nitro olefins 2. Compound 2 was prepared from glucofuranose diacetonide in three steps following the reported literature procedure.^23,24 The feasibility of the reaction between 1 and 2 was investigated by varying different reaction parameters such as in the presence of air, various bases, neat conditions and using organic solvents at rt–40 °C (Table 1).

Table 1 Optimisation of reaction conditions^a

Entry	Base	Solvent	Time	Yield^b (%)
a 1 (1 mmol), 2 (1 mmol), base (1 mmol). b Isolated yield. c Stirring at room temperature–40 ^°C. d Oil bath heating, 80 °C.
1^c	DABCO	Neat	2 h	55%
2^d	DABCO	Neat	12 h	30%
3^c	DABCO	CH3CN	2 h	50%
4^d	DABCO	CH3CN	2 h	40%
5^c	K2CO3	Neat	45 min	80%
6^c	K2CO3	Dioxane	2 h	55%
7^d	K2CO3	Dioxane	2 h	50%
8^c	Et3N	Neat	15 min	85%
9^c	DBU	Neat	2 h	30%

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Initially o-hydroxy benzaldehyde 1 was subjected to the reaction with 3-C-vinyl nitro olefins of glucose diacetonide 2 in DABCO at rt–40 °C under neat conditions. Increasing the time and temperature was deleterious to the yield of the reaction (entries 1 and 2). The same reaction was again monitored with DABCO using CH₃CN as a solvent from rt–40 °C (entries 3 and 4). But the yield of the product formed did not vary a lot. A mixture of 1, 2 and K₂CO₃ under neat conditions at room temperature was stirred for 45 min mechanically (entries 5) and the yield of the product was found to be 80%. The reaction was also tried in dioxane at room temperature and under heating conditions (entries 6 and 7). Extensive experiments revealed that the yield of product 3a was greatly affected by the use of solvents. The reaction was also performed in Et₃N under neat conditions (entries 8). Rapid conversion was observed when triethyl amine was added to a mixture of 1 and 2, and the spirocyclised product 3a was formed with 85% yield, in 15 min encouraging us to move further. Interestingly, only one enantiomer 3a was observed under all different reaction conditions. The reaction proceeded well in air or under an oxygen atmosphere. The reaction took a longer time in DBU and the yield of the product formation decreased (entries 9). All the above screening results demonstrate that the reaction proceeded to completion within 15 min in a clean manner at rt–40 °C in triethylamine.

With the optimized reaction conditions established, we further explored the substrate scope of o-hydroxy benzaldehydes and the 3-C-nitro olefin of glucofuranose diisopropylidine/dicyclohexylidine. The results are shown in Scheme 1. To our delight, the reaction exhibited a broad generality and readily afforded a variety of different 2-C-spiro-glycosyl-3-nitrochromenes 3(a–k) and 3′(a–o) in moderate to good yields with specific enantioselectivities. Notably, the reaction displayed excellent functional group compatibility for the 3-C-nitro olefin of glucofuranose dicyclohexylidine containing electron-withdrawing groups (such as –NO₂ groups) as well as electron donating groups (such as methoxy and ethoxy groups) and the corresponding products 3′(a–o) were produced in good yields in comparison to glucofuranose diacetonide 3(a–k). Generally the presence of electron rich substituents on the aromatic ring results in a higher yield of the product in both cases. The aromatic ring containing halogen substituents (dichloro, dibromo, monochloro, monobromo) were also tolerated without any difficulty except bromo-chloro substitution.

Scheme 1 Synthesis of enantiopure 2-C-spiro-glycosyl-3-nitrochromenes 3(a–k) and 3′(a–o).

When bromo chloro salicylaldehyde and 5-nitro salicylaldehyde were reacted with the 3-C-nitro olefin of glucofuranose diacetonide 2 the expected product was not formed but excitingly good yield of the product was observed in the case of dicyclohexylidine 2′. Similarly when 4-hydroxy salicylaldehyde was reacted with the 3-C-nitro olefin of glucofuranose diacetonide 2/dicyclohexylidine 2′, the desired product was not formed. The feasibility of the reaction was monitored with different bases such as DABCO, K₂CO₃, DBU and solvents as well as under neat conditions. But unfortunately we were unable to obtain our target product. Furthermore, we have increased the time and temperature of the reaction, but we noticed that increasing the time as well as the temperature of the system leads to the decomposition of the 3-C-nitro olefin of glucofuranose diacetonide 2 and regretfully, the expected product was not formed. We also observed that when naphthyl salicylaldehyde was reacted with 3-C-vinyl nitro glucofuranose diisopropylidine good yield of the product 3k was obtained as compared to 3′n which might be due to the steric effect.

It is noteworthy that the current protocol represents a new and practical pathway for assembly of richly decorated 2-C-spiro-glycosyl-3-nitrochromenes with excellent enantioselectivities through the Et₃N catalysed oxa-Michael–aldol condensation reaction of salicylaldehydes and the 3-C-nitro olefin of glucofuranose diisopropylidine/dicyclohexylidine. The structures of these spiro nitrochromenes were characterised by NMR spectroscopy and HRMS. The stereochemistry of the product was assigned by single crystal X-ray of compound 3b and the ‘S’-stereocentre was confirmed at the spirocarbon which is shown in Fig. 2. The exclusive formation of the ‘S’-stereoisomer at the spiro carbon might be controlled by the steric bulk of 1,2-diisopropylidine/cyclohexylidine of the sugar moiety.

Fig. 2 ORTEP diagram of compound 3b.

The reasonable mechanism for the formation of 3a is proposed as shown in Scheme 2. First, in the presence of a base the O-atom of 1 undergoes the Michael addition reaction with C-vinyl nitro 2 to form anion A, which then undergoes nucleophilic addition reaction with the carbonyl group of TS A to form the intermediate TS B. Subsequent dehydration of intermediate TS B in the base medium provided the desired product 3a.

Scheme 2 Proposed mechanism.

In order to extend the substrate scope of this protocol the 3-C-vinyl nitro olefin was replaced by a 3-C-vinyl ester and 3-C-vinyl nitrile in order to obtain 2-C-spiro-glycosyl-3-chromene esters/nitriles. The Michael addition reaction was also monitored in different base media such as DBU, DABCO, K₂CO₃, Et₃N etc. Unfortunately the desired product was not formed.

In summary, the first highly enantiopure synthesis of structurally diverse (2S)-2-C-spiro-glycosyl-3-nitrochromenes is described following oxa-Michael–Aldol condensation reaction. The products were obtained by the reaction of sugar derived 3C-vinyl nitro olefins with various substituted salicylaldehydes using Et₃N as base at rt–40 °C in good to excellent yield with high purity. No other external reagent or solvent was required, and also no hazardous chemical wastes were generated during the progress of the reaction. To the best of our knowledge, this strategy involves the first approach for these types of 2-C-spiro-glycosyl-3-nitrochromene derivatives and also involves a series of novel processes that are of broad interest to synthetic organic chemists.

Experimental section

General procedure for the preparation of 2-C-spiro-glycosyl-3-nitrochromenes 3

Salicylaldehyde (0.08 mmol, 1.0 equiv.), 3-C-vinyl nitro olefin of glucofuranose diisopropylidine/glucofuranose dicyclohexylidine (0.08 mmol, 1.0 equiv.) and Et₃N (0.01 mmol, 1.0 equiv.) were added in sequence and stirred mechanically at rt–40 °C under an air atmosphere for 5–15 min. After the completion of the reaction, the residue was adsorbed with silica gel and then transferred directly on to the flash column, without any additional work-up step, and was subjected to chromatographic purification using petroleum ether/ethyl acetate to give 3 in good yield (60–90%).

3-Nitromethylene-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose (2). Yellow liquid (80%); ¹H NMR (400 MHz, CDCl₃): δ_H 7.48 (1H, s, CH), 5.91 (1H, d, J = 4.0 Hz, CH), 5.81–5.80 (1H, m, CH), 4.75–4.72 (1H, m, CH), 4.15–4.12 (1H, m, CH), 4.07–4.03 (2H, m, CH₂), 1.50 (3H, s, CH₃), 1.46 (3H, s, CH₃), 1.43 (3H, s, CH₃), 1.36 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 149.2, 135.6, 113.3, 110.4, 104.8, 79.0, 78.2, 76.0, 67.3, 27.1, 27.0, 26.7, 25.0.

3-Nitromethylene-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose (2′). Yellow liquid (85%); ¹H NMR (400 MHz, CDCl₃): δ_H 7.47 (1H, s, CH), 5.91 (1H, d, J = 4.0 Hz, CH), 5.81–5.79 (1H, m, CH), 4.72–4.70 (1H, m, CH), 4.13–4.11 (1H, m, CH), 4.06–4.02 (2H, m, CH₂), 1.72–1.37 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 149.6, 135.6, 114.1, 111.1, 104.5, 79.1, 77.8, 75.7, 67.0, 36.7, 36.5, 36.5, 34.5, 24.9, 24.6, 24.0, 23.7, 23.7, 23.5.

3-Nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3a). Yellow liquid (80%); [α]²⁵_D = 405.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.95 (1H, s, CH), 7.39–7.34 (2H, m, CH), 7.09–7.08 (1H, m, CH), 6.96 (1H, d, J = 8.0 Hz, CH), 5.95 (1H, d, J = 4.0 Hz, CH), 5.48 (1H, d, J = 8.0 Hz, CH), 4.77 (1H, d, J = 4.0 Hz, CH), 4.55–4.52 (1H, m, CH), 4.21–4.15 (2H, m, CH₂), 1.56 (3H, s, CH₃), 1.34 (3H, s, CH₃), 1.28 (3H, s, CH₃), 1.23 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 152.4, 140.1, 133.8, 131.2, 130.3, 123.3, 118.8, 116.9, 113.2, 109.8, 104.2, 85.2, 80.6, 78.9, 71.8, 67.2, 26.6, 25.8, 25.4, 25.0. HRMS (ESI): calcd for C₂₀H₂₃NO₈Na [M + Na]⁺ 428.1316; found: 428.1368.

8-Methoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3b). Yellow liquid (82%); [α]²⁵_D = 445.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.93 (1H, s, CH), 7.01–6.98 (2H, m, CH), 6.95–6.94 (1H, m, CH), 5.97 (1H, d, J = 4.0 Hz, CH), 5.50 (1H, d, J = 8.0 Hz, CH), 4.74 (1H, d, J = 4.0 Hz, CH), 4.61–4.57 (1H, m, CH), 4.20–4.19 (2H, m, CH₂), 3.85 (3H, s, OCH₃), 1.56 (3H, s, CH₃), 1.35 (3H, s, CH₃), 1.28 (3H, s, CH₃), 1.23 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 148.9, 141.5, 140.3, 131.3, 123.1, 121.8, 119.6, 116.7, 113.2, 109.6, 104.3, 85.2, 80.4, 79.0, 72.0, 67.1, 56.3, 26.6, 25.9, 25.4, 25.0. HRMS (ESI): calcd for C₂₁H₂₅NO₉Na [M + Na]⁺ 458.1422; found: 458.1452.

7-Methoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3c). Yellow liquid (62%); [α]²⁵_D = 405.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.98 (1H, s, CH), 7.26 (1H, d, J = 4.0 Hz, CH), 6.62 (1H, d, J = 4.0 Hz, CH), 6.50 (1H, d, J = 2.4 Hz, CH), 5.95 (1H, d, J = 4.0 Hz, CH), 5.54 (1H, d, J = 8.0 Hz, CH), 4.77 (1H, d, J = 4.0 Hz, CH), 4.55–4.50 (1H, m, CH), 4.21–4.15 (2H, m, CH₂), 3.84 (3H, s, OCH₃), 1.55 (3H, s, CH₃), 1.34 (3H, s, CH₃), 1.28 (3H, s, CH₃), 1.25 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 164.7, 154.3, 137.1, 131.8, 131.6, 113.2, 111.7, 110.4, 109.7, 104.1, 102.1, 85.6, 80.6, 78.7, 71.9, 67.2, 55.7, 26.6, 25.8, 25.5, 25.0. HRMS (ESI): calcd for C₂₁H₂₅NO₉Na [M + Na]⁺ 458.1422; found: 458.1452.

6-Methoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3d). Yellow liquid (85%); [α]²⁵_D = 410.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.89 (1H, s, CH), 6.94–6.82 (3H, m, CH), 5.94 (1H, d, J = 4.0 Hz, CH), 5.45 (1H, d, J = 8.0 Hz, CH), 4.77 (1H, d, J = 4.0 Hz, CH), 4.55–4.52 (1H, m, CH), 4.21–4.14 (2H, m, CH₂), 3.80 (3H, s, OCH₃), 1.55(3H, s, CH₃), 1.34 (3H, s, CH₃), 1.28 (3H, s, CH₃), 1.23 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 155.4, 146.2, 140.8, 131.2, 120.1, 119.2, 117.8, 113.7, 113.2, 109.7, 104.2, 85.1, 80.1, 78.8, 71.8, 67.1, 55.8, 26.6, 25.8, 25.4, 25.0. HRMS (ESI): calcd for C₂₁H₂₅NO₉Na [M + Na]⁺ 458.1422; found: 458.1452.

8-Ethoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3e). Yellow liquid (85%); [α]²⁵_D = 600.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.93 (1H, s, CH), 7.00–6.92 (3H, m, CH), 5.96 (1H, d, J = 4.0 Hz, CH), 5.52 (1H, d, J = 8.0 Hz, CH), 4.73 (1H, d, J = 4.0 Hz, CH), 4.60–4.56 (1H, m, CH), 4.21 (2H, q, J = 8.0 Hz, CH₂), 4.08–4.06 (2H, m, CH₂), 1.55 (3H, s, CH₃), 1.40 (3H, t, J = 8.0 Hz, CH₃), 1.37 (3H, s, CH₃), 1.25 (3H, s, CH₃), 1.23 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 148.1, 141.9, 140.2, 131.4, 123.1, 122.0, 119.7, 118.8, 113.2, 109.4, 104.3, 85.3, 80.4, 79.0, 72.3, 66.8, 65.2, 26.6, 25.9, 25.5, 24.9, 14.9. HRMS (ESI): calcd for C₂₂H₂₇NO₉Na [M + Na]⁺ 472.1578; found: 472.1582.

6-Chloro-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3f). Yellow liquid (82%); [α]²⁵_D = 156.6 (c 0.06, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.86 (1H, s, CH), 7.34–7.31 (2H, m, CH), 6.95–6.91 (1H, m, CH), 5.94 (1H, d, J = 4.0 Hz, CH), 5.44 (1H, d, J = 8.0 Hz, CH), 4.74 (1H, d, J = 4.0 Hz, CH), 4.52–4.48 (1H, m, CH), 4.21–4.12 (2H, m, CH₂), 1.55 (3H, s, CH₃), 1.33 (3H, s, CH₃), 1.28 (3H, s, CH₃), 1.23 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 150.8, 141.2, 133.3, 129.7, 129.3, 128.4, 120.1, 118.3, 113.4, 109.9, 104.2, 85.5, 80.6, 78.9, 71.7, 67.2, 26.5, 25.7, 25.3, 24.9. HRMS (ESI): calcd for C₂₀H₂₂ClNO₈Na [M + H]⁺ 440.1107; found: 440.1148.

6,8-Dichloro-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3g). Yellow liquid (82%); [α]²⁵_D = 90.0 (c 0.05, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.83 (1H, s, CH), 7.43 (1H, d, J = 4.0 Hz, CH), 7.23 (1H, d, J = 2.4 Hz, CH), 5.98 (1H, d, J = 3.6 Hz, CH), 5.44 (1H, d, J = 8.0 Hz, CH), 4.68 (1H, d, J = 4.0 Hz, CH), 4.56–4.53 (1H, m, CH), 4.21–4.17 (2H, m, CH₂), 1.56 (3H, s, CH₃), 1.33 (3H, s, CH₃), 1.28 (3H, s, CH₃), 1.24 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 146.7, 142.1, 133.1, 129.0, 128.3, 127.7, 123.5, 121.0, 113.6, 109.8, 104.4, 86.2, 81.0, 79.1, 71.8, 67.1, 26.6, 25.8, 25.4, 24.9. HRMS (ESI): calcd for C₂₀H₂₁Cl₂NO₈Na [M + Na]⁺ 496.0536; found: 496.0536.

6-Bromo-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3h). Yellow liquid (82%); [α]²⁵_D = 147.0 (c 0.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.85 (1H, s, CH), 7.48–7.45 (2H, m, CH), 6.86 (1H, d, J = 8.0 Hz, CH), 5.94 (1H, d, J = 4.0 Hz, CH), 5.44 (1H, d, J = 8.0 Hz, CH), 4.74 (1H, d, J = 4.0 Hz, CH), 4.52–4.50 (1H, m, CH), 4.21–4.11 (2H, m, CH₂), 1.55 (3H, s, CH₃), 1.32 (3H, s, CH₃), 1.27 (3H, s, CH₃), 1.23 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 150.8, 141.2, 133.3, 129.7, 129.3, 128.4, 120.1, 118.3, 113.4, 109.9, 104.2, 85.5, 80.6, 78.9, 71.7, 67.2, 26.5, 25.7, 25.3, 24.9. HRMS (ESI): calcd for C₂₀H₂₂BrNO₈Na [M + Na]⁺ 506.0421; found: 506.0404.

8-Hydroxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3i). Yellow liquid, (75%); [α]²⁵_D = 97.5 (c 0.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.98 (1H, s, CH), 7.05–6.90 (3H, m, CH), 5.96 (1H, d, J = 4.0 Hz, CH), 5.49 (1H, d, J = 8.0 Hz, CH), 4.77 (1H, d, J = 4.0 Hz, CH), 4.57–4.54 (1H, m, CH), 4.24–4.12 (2H, m, CH₂), 1.83–1.66 (1H, broad singlet, OH), 1.57 (3H, s, CH₃), 1.33 (3H, s, CH₃), 1.28 (3H, s, CH₃), 1.24 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 144.9, 140.3, 138.5, 131.3, 123.9, 121.7, 120.4, 119.2, 113.5, 110.1, 104.1, 85.7, 80.3, 78.8, 71.4, 67.4, 26.5, 25.7, 25.3, 24.9. HRMS (ESI): calcd for C₂₀H₂₃NO₉Na [M + Na]⁺ 444.1265; found: 444.1262.

6-Acetyl-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3j). Yellow liquid (60%); [α]²⁵_D = −35.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.88 (1H, s, CH), 7.11–7.08 (2H, m, CH), 6.96 (1H, d, J = 8.0 Hz, CH), 5.94 (1H, d, J = 4.0 Hz, CH), 5.45 (1H, d, J = 8.0 Hz, CH), 4.79 (1H, d, J = 8.0 Hz, CH), 4.52–4.49 (1H, m, CH), 4.21–4.12 (2H, m, CH₂), 2.31 (3H, s, CH₃), 1.55 (3H, s, CH₃), 1.32 (3H, s, CH₃), 1.27 (3H, s, CH₃), 1.24 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 169.4, 149.8, 145.8, 130.3, 126.8, 122.7, 119.4, 117.7, 113.3, 109.8, 104.2, 85.4, 80.6, 78.9, 71.7, 67.2, 26.6, 25.8, 25.4, 24.9, 20.9. HRMS (ESI): calcd for C₂₂H₂₅NO₁₀ [M + H]⁺ 464.2064; found: 464.2064.

Naphthyl-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-isopropylidene-α-D-glucofuranose]chromene (3k). Yellow liquid (84%); [α]²⁵_D = 220.0 (c 0.03, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 8.68 (1H, s, CH), 8.04 (1H, d, J = 8.0 Hz, CH), 7.91 (1H, d, J = 8.0 Hz, CH), 7.82 (1H, d, J = 8.0 Hz, CH), 7.80–7.48 (2H, m, CH), 7.15(1H, d, J = 8.0 Hz, CH), 5.97 (1H, d, J = 4.0 Hz, CH), 5.57 (1H, d, J = 8.0 Hz, CH), 4.83 (1H, d, J = 4.0 Hz, CH), 4.62–4.57 (1H, m, CH), 4.25–4.17 (2H, m, CH₂), 1.58 (3H, s, CH₃), 1.37 (3H, s, CH₃), 1.29 (3H, s, CH₃), 1.21 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ_C 152.1, 137.8, 135.0, 130.7, 129.8, 129.0, 128.7, 127.8, 125.3, 121.4, 117.1, 113.2, 112.2, 109.8, 104.1, 85.6, 79.8, 78.7, 71.9, 67.2, 26.6, 25.9, 25.4, 25.0. HRMS (ESI): calcd for C₂₄H₂₅NO₈Na [M + Na]⁺ 478.1472; found: 478.1474.

3-Nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-gluco-furanose]chromene (3′a). Yellow liquid (80%); [α]²⁵_D = 355.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.95 (1H, s, CH), 7.38–7.32 (2H, m, CH), 7.08–7.06 (1H, m, CH), 6.95 (1H, d, J = 8.0 Hz, CH), 5.95 (1H, d, J = 4.0 Hz, CH), 5.45 (1H, d, J = 8.0 Hz, CH), 4.76 (1H, d, J = 4.0 Hz, CH), 4.54–4.49 (1H, m, CH), 4.20–4.11 (2H, m, CH₂), 1.81–1.24 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 152.4, 140.3, 133.8, 131.0, 130.3, 123.2, 118.7, 116.9, 114.2, 110.4, 103.9, 85.4, 80.5, 79.1, 71.4, 67.0, 36.1, 35.5, 35.3, 34.4, 25.0, 24.7, 23.9, 23.8, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₃₁NO₈Na [M + Na]⁺ 508.1942; found: 508.1941.

8-Methoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′b). Yellow liquid (84%); [α]²⁵_D = 254.2 (c 0.07, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.94 (1H, s, CH), 7.01–6.94 (3H, m, CH), 5.98 (1H, d, J = 4.0 Hz, CH), 5.48 (1H, d, J = 8.0 Hz, CH), 4.74 (1H, d, J = 4.0 Hz, CH), 4.59–4.56 (1H, m, CH), 4.21–4.13 (2H, m, CH₂), 3.85 (3H, s, OCH₃), 1.76–1.21 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 148.8, 141.5, 140.6, 131.2, 123.0, 121.8, 119.6, 116.6, 114.1, 110.3, 104.0, 85.4, 80.1, 79.1, 71.6, 66.9, 56.3, 35.7, 35.5, 35.3, 34.3, 25.1, 24.7, 23.9, 23.8, 23.6, 23.4. HRMS (ESI): calcd for C₂₇H₃₃NO₉ [M]⁺ 515.1840; found: 515.1840.

7-Methoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′c). Yellow liquid (75%); [α]²⁵_D = 405.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.98 (1H, s, CH), 7.26 (1H, d, J = 1.6 Hz, CH), 6.63–6.60 (1H, m, CH), 6.50 (1H, d, J = 2.0 Hz, CH), 5.95 (1H, d, J = 4.0 Hz, CH), 5.52 (1H, d, J = 8.0 Hz, CH), 4.76 (1H, d, J = 4.0 Hz, CH), 4.51–4.46 (1H, m, CH), 4.20–4.10 (2H, m, CH₂), 3.83 (3H, s, OCH₃), 1.83–1.16 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 164.7, 154.4, 137.3, 131.7, 131.5, 114.1, 111.7, 110.4, 110.3, 103.8, 102.0, 85.7, 80.4, 78.9, 71.5, 67.0, 55.7, 36.1, 35.5, 35.3, 34.5, 25.0, 24.7, 23.9, 23.8, 23.7, 23.4. HRMS (ESI): calcd for C₂₇H₃₃NO₉ [M]⁺ 515.1840; found: 515.1840.

6-Methoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′d). Yellow liquid (90%); [α]²⁵_D = 177.5 (c 0.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.91 (1H, s, CH), 6.93–6.83 (3H, m, CH), 5.93 (1H, d, J = 4.0 Hz, CH), 5.43 (1H, d, J = 8.0 Hz, CH), 4.76 (1H, d, J = 3.6 Hz, CH), 4.53–4.48 (1H, m, CH), 4.20–4.08 (2H, m, CH₂), 3.80 (3H, s, OCH₃), 1.81–1.21 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 155.3, 146.3, 141.0, 131.1, 120.0, 119.2, 117.7, 114.1, 113.6, 110.4, 103.9, 85.2, 79.9, 79.0, 71.4, 67.0, 55.8, 36.1, 35.4, 35.3, 34.4, 25.1, 24.7, 23.9, 23.8, 23.6, 23.4. HRMS (ESI): calcd for C₂₇H₃₃NO₉ [M]⁺ 515.1840; found: 515.1840.

8-Ethoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′e). Yellow liquid (90%); [α]²⁵_D = 112.5 (c 0.04, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.93 (1H, s, CH), 6.99–6.92 (3H, m, CH), 5.95 (1H, d, J = 4.0 Hz, CH), 5.49 (1H, d, J = 8.0 Hz, CH), 4.72 (1H, d, J = 4.0 Hz, CH), 4.57–4.54 (1H, m, CH), 4.18–4.08 (2H, m, CH₂), 4.07 (2H, q, J = 8.0 Hz, OCH₂), 1.68–1.47 (13H, m, CH₂), 1.39 (3H, t, J = 8.0 Hz, CH₃), 1.35–1.23 (7H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 148.0, 142.1, 140.5, 131.2, 123.0, 122.1, 119.7, 118.9, 114.1, 110.1, 104.0, 85.4, 80.2, 79.2, 71.8, 66.7, 65.3, 36.2, 35.6, 35.3, 34.4, 25.1, 24.7, 23.9, 23.8, 23.7, 23.5, 14.9. HRMS (ESI): calcd for C₂₈H₃₅NO₉Na [M + Na]⁺ 552.2204; found: 552.2201.

6-Chloro-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′f). Yellow liquid (85%); [α]²⁵_D = 140.0 (c 0.07, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.86 (1H, s, CH), 7.34–7.31 (2H, m, CH), 6.91 (1H, d, J = 8.0 Hz, CH), 5.95 (1H, d, J = 4.0 Hz, CH), 5.42 (1H, d, J = 8.0 Hz, CH), 4.74 (1H, d, J = 4.0 Hz, CH), 4.50–4.46 (1H, m, CH), 4.20–4.08 (2H, m, CH₂), 1.81–1.23 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 150.8, 141.4, 133.3, 129.6, 129.3, 128.2, 120.0, 118.2, 114.4, 110.5, 103.9, 85.6, 80.5, 79.1, 71.3, 67.1, 36.1, 35.4, 35.2, 34.3, 25.0, 24.7, 23.9, 23.7, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₃₀ClNO₈Na [M + Na]⁺ 542.1552; found: 542.1553.

6,8-Dichloro-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′g). Yellow liquid (85%); [α]²⁵_D = 152.0 (c 0.05, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.82 (1H, s, CH), 7.42 (1H, d, J = 1.2 Hz, CH), 7.23 (1H, d, J = 4.0 Hz, CH), 5.99 (1H, d, J = 4.0 Hz, CH), 5.42 (1H, d, J = 8.0 Hz, CH), 4.68 (1H, d, J = 4.0 Hz, CH), 4.53–4.49 (1H, m, CH), 4.22–4.11 (2H, m, CH₂), 1.80–1.25 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 146.8, 142.4, 133.0, 128.8, 128.2, 127.6, 123.4, 121.0, 114.6, 110.5, 104.1, 86.4, 80.9, 79.3, 71.5, 67.0, 36.1, 35.5, 35.3, 34.3, 25.0, 24.6, 23.9, 23.7, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₂₉Cl₂NO₈Na [M + Na]⁺ 576.1162; found: 576.1165.

6-Bromo-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′h). Yellow liquid (85%); [α]²⁵_D = 110.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.85 (1H, s, CH), 7.53–7.40 (2H, m, CH), 6.87 (1H, d, J = 8.0 Hz, CH), 5.94 (1H, d, J = 4.0 Hz, CH), 5.42 (1H, d, J = 8.0 Hz, CH), 4.73 (1H, d, J = 3.6 Hz, CH), 4.50–4.42 (1H, m, CH), 4.20–4.08 (2H, m, CH₂), 1.94–1.25 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 151.2, 141.3, 136.0, 132.1, 129.3, 120.4, 118.5, 115.2, 114.2, 110.4, 103.8, 85.5, 80.5, 79.0, 71.2, 67.0, 36.0, 35.3, 35.1, 34.3, 24.9, 24.6, 23.8, 23.7, 23.5, 23.3. HRMS (ESI): calcd for C₂₆H₃₀BrNO₈Na [M + Na]⁺ 586.1047; found: 586.1047.

6,8-Dibromo-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′i). Yellow liquid (70%); [α]²⁵_D = 245.7 (c 0.07, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.82 (1H, s, CH), 7.71 (1H, d, J = 2.0 Hz, CH), 7.41 (1H, d, J = 4.0 Hz, CH), 6.00 (1H, d, J = 4.0 Hz, CH), 5.42 (1H, d, J = 8.0 Hz, CH), 4.67 (1H, d, J = 4.0 Hz, CH), 4.53–4.49 (1H, m, CH), 4.22–4.12 (2H, m, CH₂), 1.86–1.14 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 148.4, 142.3, 138.5, 131.2, 128.8, 121.3, 115.4, 114.7, 112.1, 110.5, 104.1, 86.5, 80.9, 79.3, 71.6, 67.0, 36.1, 35.5, 35.2, 34.3, 25.0, 24.6, 23.9, 23.7, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₂₉Br₂NO₈ [M]⁺ 642.9881; found: 642.9881.

8-Hydroxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′j). Yellow liquid (80%); [α]²⁵_D = 126.6 (c 0.06, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 7.99 (s, 1H, CH), 7.04–6.91 (m, 3H, CH), 6.24 (broad singlet, 1H, OH), 5.95 (d, J = 4.0 Hz, 1H, CH), 5.48 (d, J = 8.0 Hz, 1H, CH), 4.76 (d, J = 4.0 Hz, 1H, CH), 4.56–4.51 (m, 1H, CH), 4.23–4.09 (m, 2H, CH₂), 1.82–1.25 (m, 20H, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ 144.9, 140.4, 138.7, 131.2, 123.8, 121.6, 120.4, 119.1, 114.5, 110.7, 103.7, 85.8, 80.0, 79.0, 71.0, 67.1, 36.0, 35.3, 35.1, 34.3, 25.0, 24.6, 23.9, 23.7, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₃₁NO₉Na [M + Na]⁺ 524.1891; found: 524.1793.

6-Hydroxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′k). Yellow liquid (85%); [α]²⁵_D = 80.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.85 (1H, s, CH), 6.84–6.75 (3H, m, CH), 5.94 (1H, d, J = 4.0 Hz, CH), 5.72 (1H, broad singlet, OH), 5.45 (1H, d, J = 12.0 Hz, CH), 4.76 (1H, d, J = 4.0 Hz, CH), 4.56–4.51 (1H, m, CH), 4.21–4.11 (2H, m, CH₂), 1.79–1.15 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 151.5, 146.0, 140.9, 131.0, 120.8, 119.3, 117.8, 115.7, 114.2, 110.6, 103.8, 85.1, 79.9, 79.0, 71.4, 67.0, 36.1, 35.4, 35.2, 34.4, 25.0, 24.7, 23.9, 23.8, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₃₁NO₉Na [M + Na]⁺ 524.1891; found: 524.1793.

6-Bromo-8-methoxy-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′l). Yellow liquid (60%); [α]²⁵_D = 85.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.82 (1H, s, CH), 7.07 (2H, s, CH), 5.96 (1H, d, J = 4.0 Hz, CH), 5.43 (1H, d, J = 8.0 Hz, CH), 4.71 (1H, d, J = 4.0 Hz, CH), 4.53–4.49 (1H, m, CH), 4.20–4.10 (2H, m, CH₂), 3.84 (3H, s, OCH₃), 1.80–1.25 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 149.5, 141.5, 140.7, 129.7, 123.6, 120.7, 119.2, 114.9, 114.3, 110.4, 104.0, 85.6, 80.2, 79.1, 71.5, 67.0, 56.4, 36.1, 35.5, 35.3, 34.3, 25.0, 24.7, 23.9, 23.8, 23.6, 23.4. HRMS (ESI): calcd for C₂₇H₃₂BrNO₉ [M]⁺ 593.0919; found: 593.0919.

8-Bromo-6-chloro-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′m). Yellow liquid (70%); [α]²⁵_D = 100.0 (c 0.03, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 7.82 (1H, s, CH), 7.58 (1H, s, CH), 7.30–7.26 (1H, m, CH), 6.00 (1H, d, J = 4.0 Hz, CH), 5.42 (1H, d, J = 8.0 Hz, CH), 4.67 (1H, d, J = 4.0 Hz, CH), 4.54–4.50 (1H, m, CH), 4.22–4.14 (2H, m, CH₂), 1.73–1.13 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 148.4, 142.3, 138.5, 131.2, 128.8, 121.3, 115.4, 114.7, 112.1, 110.5, 104.1, 86.5, 80.9, 79.3, 71.6, 67.0, 36.1, 35.5, 35.2, 34.3, 25.0, 24.6, 23.9, 23.7, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₂₉BrClNO₈Na [M + Na]⁺ 620.0658; found: 620.0658.

Naphthyl-3-nitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′n). Yellow liquid (61%); [α]²⁵_D = −45.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 8.70 (1H, s, CH), 8.07 (1H, d, J = 8.0 Hz, CH), 7.91 (1H, d, J = 8.0 Hz, CH), 7.83 (1H, d, J = 8.0 Hz, CH), 7.69–7.45 (2H, m, CH), 7.15 (1H, d, J = 8.0 Hz, CH), 5.97 (1H, d, J = 4.0 Hz, CH), 5.56 (1H, d, J = 12.0 Hz, CH), 4.83 (1H, d, J = 4.0 Hz, CH), 4.62–4.51 (1H, m, CH), 4.24–4.13 (2H, m, CH₂), 1.82–1.14 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 152.2, 139.8, 134.9, 130.7, 129.8, 128.9, 128.6, 127.7, 125.3, 121.4, 117.2, 114.2, 112.1, 110.4, 103.8, 85.7, 79.6, 78.8, 71.5, 67.1, 36.1, 35.5, 35.2, 34.4, 25.0, 24.7, 23.9, 23.7, 23.6, 23.4. HRMS (ESI): calcd for C₃₀H₃₃NO₈Na [M + Na]⁺ 558.2098; found: 558.2010.

3,6-Dinitro-2-C-[3-spiro-1,2,5,6-di-O-cyclohexylidene-α-D-glucofuranose]chromene (3′o). Yellow liquid (65%); [α]²⁵_D = −75.0 (c 0.02, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ_H 8.22–8.21 (2H, m, CH), 7.87 (1H, s, CH), 7.02 (1H, d, J = 8.0 Hz, CH), 5.92 (1H, d, J = 4.0 Hz, CH), 5.37 (1H, d, J = 12.0 Hz, CH), 4.66 (1H, d, J = 4.0 Hz, CH), 4.41–4.36 (1H, m, CH), 4.06–4.02 (2H, m, CH₂), 1.54–1.28 (20H, m, CH₂); ¹³C NMR (100 MHz, CDCl₃): δ_C 157.0, 143.1, 142.1, 128.7, 128.4, 125.5, 118.8, 117.4, 114.8, 110.7, 103.9, 86.8, 81.8, 79.4, 71.3, 67.1, 36.0, 35.3, 35.2, 34.2 249, 24.6, 23.9, 23.7, 23.6, 23.4. HRMS (ESI): calcd for C₂₆H₃₀N₂O₁₀Na [M + Na]⁺ 553.1792; found: 553.1792.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

SN and SRM are thankful to the CSIR New Delhi [02(0218)/14/EMR-II] and the DRDO New Delhi ERIP/ER/1203083/M/01/1643 for providing research grant and also thankful to DST-FIST New Delhi for providing NMR facility. PP is thankful to DST, Odisha, No. 27562800382017/202519 for Biju Patnaik research fellowship.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1869383. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ob02278j

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