Leuckart–Wallach Approach to Sugar Isocyanides and Its IMCRs

Abstract

We utilize our recently introduced Leuckart–Wallach approach to synthesize anomeric sugar isocyanides in good overall yields and two steps. Moreover, we show the general usage of these isocyanides in isocyanide-based multicomponent reactions (IMCRs) to produce eight different compounds/scaffolds.

Chimeric compounds of a sugar and organic moiety are an interesting class of compounds with important applications in medicine and great potential for drug discovery.[1] [2] [3] [4] Recently approved examples of such synthetic chimeras include Sofosbuvir (1, hepatitis C),[5] Acarbose (2, diabetes),[6] and Mifamurtide (3, anticancer),[7] just to name a few (Figure [1]). Sugar moieties in drugs are used for different purposes, e.g. the glycosyl substituent will be recognized by the receptor and contribute directly to the biological activity or it helps to improve transport properties through transporters and increase water solubility. Glycosyl-organic fragment chimeras are traditionally synthesized by sequential multistep synthesis; however multicomponent reaction (MCR) chemistry is not only efficient and short, but also a diverse alternative.[8] [9] A major group of multicomponent reactions are based on the unusual reactivity of isocyanides, isocyanide multicomponent reactions (IMCRs).[10] Glycosyl isocyanides are known and have been sporadically used in IMCRs­,[11] [12] however they are rather complex to synthesize via anomeric glycosyl fluorides or bromides[13] [14] [15] [16] mostly using CN^–, from the glycosyl isothiocyanate[17] via reduction or classically and most commonly using the Ugi approach (NH₂ → NHCHO → NC) from the anomeric amine (Scheme [1]).[18] [19] [20] [21] [22] [23] These methods either give complex mixtures (with AgCN), use harsh conditions (boiling xylene), expensive materials, limited applications, and lengthy syntheses (4–6 steps from the sugar) based on potentially dangerous azides. To revive the field of glyco-based IMCR and in continuation of our interest in this area, we introduce here a short and convenient synthesis of glycosyl and arabinosyl isocyanides directly from the sugar via a two-step procedure involving our recently published modified Leuckart–Wallach procedure.[24] [25] Moreover, we exemplify the unprecedented use of arabinosyl and glucosyl isocyanides in six different IMCRs.

We envisaged the use of the Leuckart–Wallach reaction on two basic and quite representative sugars, α-d-glucose and l-arabinose respectively. After the per-O-acetylation followed by exclusive deprotection of the anomeric hydroxyl group, we performed the aforementioned reaction of the reductive amination using both microwave and by conventional heating (Scheme [2]).[24] Interestingly, we obtained the corresponding formamides 6 and 7 in moderate to good yields and typical dehydration either with phosphoryl chloride or triphosgene led to the isocyanides 8 and 9 respectively (Scheme [2]).

Surprisingly, the Leuckart–Wallach reaction of 4, afforded almost exclusively the β-anomer 6 with Z-configuration[18] [26] and subsequently β-isocyanide 8. The stereoselectivity of our method in the case of d-glucose is worth mentioning as most times using enantiomerically pure starting materials gave α/β mixtures of the isocyanide with cis and trans conformation. We speculate that the selective cis-6-β-anomer formation is due to the formation of a preferred hydrogen bonding of the formamide NH with a neighboring acetyl group. On the other hand the formamide 7 was formed as a complex anomeric mixture most likely because of the sterical hindrance of the acetoxymethyl group in the 6-position. Initially the arabinosyl isocyanide was obtained as a mixture of anomers (9a/9b, 1:2) in 72% overall yield, but it was possible to separate them by column chromatography (Scheme [2]).

Having established the synthesis of the isocyanides 8 and 9a,b in only two steps from the readily available starting materials 4 and 5, respectively, we tested their application by employing them in IMCRs. Since the application of the sugar isocyanides in multicomponent reactions is limited, we demonstrated their utility by performing six different reactions leading to diverse scaffolds. Various aldehydes, amines, and acids were used in order to illustrate the diversity and complexity that can be achieved. Thus, the glycosyl isocyanide 8 was successfully utilized in the Ugi four-component (U-4CR), Ugi tetrazole (UT-4CR), Ugi β-lactam, and Passerini three-component (P-3CR) reactions (Scheme [3]) yielding compounds 10–13. The reactions proceeded at room temperature or under microwave irradiation giving good to very good yields; no epimerization on the α-carbon of the isocyanide was observed.

After these successful efforts, we decided to investigate the arabinosyl isocyanide. We selected the separated β-anomer 9b and we performed Passerini, Ugi tetrazole variation bearing a free amino group, a Gröbcke–Blackburn–Bienaymé­ (GBB-3CR), and finally Ugi five-center four-component (U-5C-4CR) reactions (Scheme [4]) yielding compounds 14–17. It seems that this isocyanide is less reactive, so only under microwave conditions we were able to obtain the desired products in acceptable yields. In both cases of the two isocyanides, we wanted to employ druglike moieties, like tetrazoles (compounds 11, 15), aminopyridines (compound 14), piperidines (compound 17), and lactams (compound 12), which along with the sugar moiety demonstrate the usefulness of these multicomponent reactions.

In conclusion, we have prepared sugar isocyanides through a novel synthetic pathway, the Leuckart–Wallach route, and we demonstrated their utilization in multicomponent chemistry. Our method is shorter, higher yielding, and less expensive compared to previously reported glycosyl isocyanide syntheses and, therefore, we foresee widespread use in future synthetic applications. The IMCR examples presented herein illustrate the generality and the broad scope and we believe that this application will be very useful to both multicomponent reactions and carbohydrate chemistry.

NMR spectra were recorded on a Bruker Avance 500 spectrometer [¹H NMR (500 MHz), ¹³C NMR (126 MHz)]; ¹³C NMR are reported relative to the solvent peak. TLC was performed on Fluka precoated silica gel plates (0.20-mm thick, particle size 25 μm). Flash chromatography was performed on a Teledyne ISCO Combiflash Rf, using RediSep Rf Normal-phase Silica Flash Columns (Silica Gel 60 Å, 230–400 mesh) and on a Reveleris^® X2 Flash Chromatography, using Grace^® Reveleris Silica flash cartridges (12 g). PE = Petroleum ether. Reagents were available from commercial suppliers (Sigma Aldrich, ABCR, Acros, and AK Scientific) and used without purification unless otherwise noted. All microwave irradiation reactions were carried out in a Biotage Initiator™ Microwave Synthesizer. Electrospray ionization mass spectra (ESI-MS) were recorded on a Waters Investigator Semi-prep 15 SFC-MS instrument.

2,3,4,6-Tetra-O-acetyl-d-mannopyranose (4)[27]

To a stirred solution of 1,2,3,4,6-penta-O-acetyl-α-d-mannopyranose (3.0 mmol; anomeric ratio α/β, 10:1) [prepared by adding Ac₂O (85.0 mmol) dropwise to a stirred solution of d-glucose (11.0 mmol) at 0 °C; the mixture was then stirred at r.t. overnight] in THF (15 mL), 2 M MeNH₂ in MeOH (3.5 mL) was added. The mixture was stirred at r.t. for 2 h, and then it was concentrated in vacuo and the residue was purified by column chromatography to afford 4 as an oil; yield: 940 mg (90%); R_f = 0.49 (EtOAc–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ (mixture of anomers, α/β, 3:1) = 5.54 (t, J = 9.8 Hz, 1 H), 5.47 (t, J = 3.0 Hz, 1 H), 5.26 (t, J = 9.5 Hz, 1 H), 5.09 (t, J = 9.8 Hz, 1 H), 4.92–4.90 (m, 1 H), 4.75 (t, J = 8.4 Hz, 1 H), 4.27–4.25 (m, 1 H), 4.15–4.12 (m, 1 H), 3.76 (dq, J = 9.8, 2.4 Hz, 1 H), 3.69 (d, J = 8.4 Hz, 1 H), 3.32 (d, J = 3.0 Hz, 1 H), 2.10–2.02 (m, 12 H).

2,3,4-Tri-O-acetyl-d-arabinopyranose (5)

To a stirred solution of 1,2,3,4-tetra-O-acetyl-α-d-arabinopyranose (3.0 mmol; anomeric ratio α/β, 2:1) [prepared by adding Ac₂O (85.0 mmol) dropwise to a stirred solution of d-arabinose (11.0 mmol) at 0 °C; the mixture was stirred at r.t. overnight] in THF (15 mL), 2 M MeNH₂ in MeOH (3.5 mL) was added. The mixture was stirred at r.t. for 2 h, and then the mixture was concentrated in vacuo and the residue was purified by column chromatography to afford 5 as an oil; 696 mg (84%); R_f = 0.39 (EtOAc–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ (mixture of anomers, α/β, 2:1) = 5.49 (d, J = 0.5 Hz, 1 H), 5.41 (dd, J = 5, 0.5 Hz, 1 H), 5.36 (br s, 1 H), 5.20 (dd, J = 10, 0.5 Hz, 1 H), 5.09 (br s, 1 H), 4.63 (d, J = 5 Hz, 1 H), 4.21 (d, J = 15 Hz, 1 H), 4.04 (dd, J = 10, 5 Hz, 1 H), 3.71 (td, J = 10, 5 Hz, 2 H), 2.15 (s, 3 H), 2.11 (s, 3 H), 2.03 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 171.4, 170.6, 170.3, 91.2, 71.5, 68.1, 67.1, 60.6, 21.2, 21.1, 20.9.

2,3,4,6-Tetra-O-acetyl-N-formyl-β-d-glucopyranosylamine (6);[18] [25] Typical Procedure

A solution of compound 4 (2.0 mmol) in formamide (100.0 mmol) and formic acid (10.0 mmol) was refluxed at 140 °C for 3 h. The mixture was cooled and then extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were washed with water, dried (MgSO₄), filtered, and concentrated in vacuo. Alternatively (with no significant effect on the yield), a solution of compound 4 (2.0 mmol) in formamide (100.0 mmol) and formic acid (10.0 mmol) was irradiated in a microwave oven at 180 °C for 3 min (attention: during irradiation, pressure develops). Flash chromatography (silica gel) afforded 6 as transparent crystals; yield: 412 mg (55%); R_f = 0.21 (EtOAc–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ (Z-isomer) = 8.22 (s, 1 H), 6.37 (br s, 1 H, NH), 5.32 (td, J = 10, 5 Hz, 2 H), 5.07 (t, J = 5 Hz, 1 H), 4.95 (t, J = 10 Hz, 1 H), 4.32 (dd, J = 10, 5 Hz, 1 H), 4.10 (dd, J = 10, 5 Hz, 1 H), 2.09 (s, 3 H), 2.07 (s, 3 H), 2.04 (s, 3 H), 2.03 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 171.3, 171.0, 170.1, 169.8, 161.2, 76.8, 74.0, 72.8, 70.6, 68.3, 61.8, 20.93, 20.87, 20.8, 20.75.

2,3,4-Tetra-O-acetyl-N-formyl-d-glucopyranosylamine (7)

Following the typical procedure for 6 using 5 gave 7 as transparent crystals; yield: 376 mg (62%); R_f = 0.25 (EtOAc–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ (mixture of anomers) = 8.23 (s, 1 H), 6.43 (br s, 1 H, NH), 5.35 (s, 2 H), 5.19 (t, J = 10 Hz, 2 H), 5.15 (t, J = 5 Hz, 2 H), 4.01 (dd, J = 10, 5 Hz, 2 H), 3.80 (d, J = 15 Hz, 1 H), 2.16 (s, 3 H), 2.08 (s, 3 H), 2.03 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.3, 170.1, 170.0, 161.3, 77.6, 70.6, 68.6, 68.3, 66.2, 21.1, 20.9, 20.8.

(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-isocyanotetrahydro-2H-pyran-3,4,5-triyl Triacetate (8);[18] Typical Procedure

To a solution of the formamide 6 (3.0 mmol) in CH₂Cl₂ (15 mL), Et₃N (15.0 mmol) was added. The mixture was stirred at 0 °C, then POCl₃ (3.3 mmol) was added dropwise over 15 min. The solution was stirred at r.t. for 3 h and then it was quenched with sat. NaHCO₃. The organic layer was separated, washed with water, dried (MgSO₄), filtered, and concentrated in vacuo. Flash chromatography (silica gel, CH₂Cl₂) afforded 8 as a yellow solid; yield: 696 mg (65%); R_f = 0.72 (EtOAc­–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ (β-anomer) = 5.20–5.10 (m, 3 H), 4.83 (d, J = 5 Hz, 1 H), 4.26 (dd, J = 10, 5 Hz, 1 H), 4.15 (dd, J = 10, 5 Hz, 1 H), 3.74 (ddd, J = 10, 5, 2 Hz, 1 H), 2.12 (s, 3 H), 2.12 (s, 3 H), 2.04 (s, 3 H), 2.02 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.5, 170.0, 169.1, 168.9, 164.8 (br s, NC), 100.0, 79.4, 74.7, 72.1, 71.1, 67.3, 61.3, 20.7, 20.5, 20.4.

(2S,3S,4R,5R)-2-Isocyanotetrahydro-2H-pyran-3,4,5-triyl Triacetate (9a) and (2R,3S,4R,5R)-2-Isocyanotetrahydro-2H-pyran-3,4,5-triyl Triacetate (9b)

Following the typical procedure for 8 using 7 gave 9 as a yellow solid; yield: 616 mg (72%); R_f = 0.75 (EtOAc–PE, 1:1); mixture of anomers (α/β, 1:2). Purification by column chromatography afforded anomers 9a and 9b.

α-Anomer 9a

Yellow solid; yield: 205 mg (24%); R_f = 0.75.

¹H NMR (500 MHz, CDCl₃): δ = 5.58 (d, J = 5 Hz, 1 H), 5.41 (br s, 1 H), 5.30 (dd, J = 10, 5 Hz, 1 H), 5.19 (dd, J = 5, 0.5 Hz, 1 H), 4.11 (d, J = 15 Hz, 1 H), 3.96 (dd, J = 10, 5 Hz, 1 H), 2.16 (s, 3 H), 2.15 (s, 3 H), 2.04 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.1, 170.0, 169.7, 164.6 (br s, NC), 79.8, 67.2, 66.7, 66.0, 63.4, 20.8, 20.6, 20.6.

β-Anomer 9b

Yellow solid; yield: 410 mg (48%); R_f = 0.75.

¹H NMR (500 MHz, CDCl₃): δ = 5.27–5.24 (m, 1 H), 5.23–5.22 (m, 1 H), 5.16 (dd, J = 10, 5 Hz, 1 H), 4.94 (d, J = 5 Hz, 1 H), 4.12 (dd, J = 10, 5 Hz, 1 H), 3.78 (dd, J = 5, 0.5 Hz, 1 H), 2.15 (s, 3 H), 2.13 (s, 3 H), 2.12 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.1, 169.9, 169.2, 164.2 (br s, NC), 78.7, 69.0, 38.1, 65.6, 62.3, 21.0, 20.9, 20.8.

(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-{[2-(N-(4-methoxybenzyl)formamido]-2-(p-tolyl)acetamido}tetrahydro-2H-pyran-3,4,5-triyl Triacetate (10)

To a solution of 4-methoxybenzylamine (0.2 mmol) in MeOH (1 mL), 4-methylbenzaldehyde (0.2 mmol), isocyanide 8 (0.2 mmol), and formic acid (0.2 mmol) were added. The mixture was stirred at r.t. for 24 h. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2) to afford 10 as a yellow oil; yield: 58 mg (45%); R_f = 0.20 (EtOAc–PE, 1:1); mixture of rotamers and mixture of diastereomers (dr 2:1).

¹H NMR (500 MHz, CDCl₃): δ = 8.29 (s, 1 H), 8.26 (s, 1 H), 7.13–7.09 (m, 5 H), 7.03 (d, J = 10 Hz, 1 H), 6.96 (d, J = 10 Hz, 1 H), 6.86–6.85 (m, 1 H), 6.79 (t, J = 10 Hz, 1 H), 6.41–6.36 (m, 1 H), 5.33–5.22 (m, 3 H), 5.04–4.99 (m, 1 H), 4.88–4.76 (m, 1 H), 4.50–4.43 (m, 1 H), 4.36–4.27 (m, 1 H), 4.21–4.05 (m, 2 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 2.35 (s, 3 H), 2.33 (s, 3 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 171.7, 170.9, 170.1, 169.7, 163.7, 163.5, 130.2, 130.0, 129.7, 129.4, 129.4, 128.7, 114.4, 114.3, 78.9, 78.5, 73.7, 72.9, 70.4, 72.9, 70.4, 70.1, 68.5, 68.4, 61.9, 61.8, 61.1, 55.5, 49.9, 21.4, 20.9, 20.8.

MS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₃₈N₂O₁₂: 665.24; found: 665.14.

(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-{5-[(phenethylamino)(p-tolyl)methyl]-1H-tetrazol-1-yl}tetrahydro-2H-pyran-3,4,5-triyl Triacetate (11)

To a solution of phenylethylamine (0.5 mmol) in MeOH (1 mL), 4-methylbenzaldehyde (0.5 mmol), isocyanide 8 (0.5 mmol), and TMSN₃ (0.5 mmol) were added. The mixture was stirred at r.t. for 24 h. Alternatively (with no significant effect on the yield), a solution of phenylethylamine (0.5 mmol), 4-methylbenzaldehyde (0.5 mmol), isocyanide 6 (0.5 mmol), and TMSN₃ (0.5 mmol) in MeOH (1 mL) was irradiated in a microwave oven at 100 °C for 30 min. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2) to afford 11 as a yellow oil; yield: 193 mg (62%); R_f = 0.25 (EtOAc–PE, 1:1); mixture of diastereomers (dr 1:0.8).

¹H NMR (500 MHz, CDCl₃): δ = 7.34–7.31 (m, 3 H), 7.25–7.17 (m, 9 H), 7.16 (br s, 4 H), 6.08 (d, J = 10 Hz, 1 H), 6.03 (d, J = 10 Hz, 1 H), 5.90 (t, J = 10 Hz, 1 H), 5.43 (s, 1 H), 5.36 (s, 1 H), 5.29–5.16 (m, 4 H), 4.17–4.10 (m, 3 H), 3.96 (dd, J = 15, 0.5 Hz, 1 H), 3.79 (dd, J = 10, 0.5 Hz, 1 H), 3.58 (dt, J = 10, 10 Hz, 1 H), 3.57–3.56 (m, 1 H), 2.91–2.82 (m, 7 H), 2.34 (s, 3 H), 2.33 (s, 3 H), 2.11 (s, 3 H), 2.10 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.52, 170.5, 169.2, 168.3, 156.9, 139.4, 138.8, 134.6, 129.9 (2 CH_Ph), 128.8 (4 CH_Ar), 127.0 (2 CH_Ph), 126.7, 83.0, 74.8, 73.4, 69.6, 67.5, 61.2, 57.9, 48.8, 36.2, 21.2, 20.8, 20.7, 20.3, 20.1.

MS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₇N₅O₉: 624.26; found: 624.17.

(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-[2-(4-bromophenyl)-2-(2-oxoazetidin-1-yl)acetamido]tetrahydro-2H-pyran-3,4,5-triyl Tri­acetate (12)

A solution of 4-bromobenzaldehyde (0.5 mmol), β-alanine (0.5 mmol), and the isocyanide 8 (0.5 mmol) in MeOH (1 mL) was irradiated in a microwave oven at 100 °C for 30 min. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2) to afford 12 as a yellow oil; yield: 202 mg (66%); R_f  = 0.10 (EtOAc–PE, 1:1); mixture of diastereomers (dr 1:1).

¹H NMR (500 MHz, CDCl₃): δ = 7.53 (d, J = 10 Hz, 2 H), 7.18 (d, J = 10 Hz, 2 H), 5.35–5.23 (m, 3 H), 5.06–5.03 (m, 2 H), 4.92–4.83 (m, 1 H), 4.35–4.27 (m, 2 H), 4.11–4.07 (m, 2 H), 3.83–3.79 (m, 2 H), 3.59–3.57 (m, 1 H), 3.49–3.48 (m, 1 H), 3.13–3.01 (m, 2 H), 2.90–2.88 (m, 1 H), 2.04 (m, 3 H), 2.03 (m, 3 H), 2.01 (m, 3 H), 2.00 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.9, 170.4, 169.3, 168.0, 153.2, 132.7, 132.6, 130.4, 130.2, 100.3, 78.9, 74.0, 72.8, 72.6, 70.4, 68.3, 61.7, 59.0, 39.3, 38.9, 36.7, 36.6, 20.9, 20.8, 20.7.

MS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₂₉BrN₂O₁₁: 635.10; found: 635.01.

(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-[1-(benzoyloxy)cyclohexanecarboxamido]tetrahydro-2H-pyran-3,4,5-triyl Triacetate (13)

To a solution of cyclohexanone (0.5 mmol) in CH₂Cl₂ (1 mL), benzoic acid (0.5 mmol), and isocyanide 8 (0.5 mmol) were added. The mixture was stirred at r.t. for 24 h. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2) to afford 13 as a white solid; yield: 136 mg (47%); R_f = 0.39 (EtOAc­–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ = 8.04 (d, J = 5 Hz, 1 H), 7.64–7.59 (m, 1 H), 7.51–7.46 (m, 2 H), 6.66 (d, J = 10 Hz, 1 H), 5.32–5.27 (m, 1 H), 5.06–4.98 (m, 1 H), 4.89–4.85 (t, J = 10 Hz, 1 H), 4.33 (dd, J = 10, 0.5 Hz, 1 H), 4.11–4.04 (m, 2 H), 3.86–3.80 (m, 1 H), 2.41–2.38 (m, 1 H), 2.34–2.35 (m, 1 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 3 H), 1.98 (s, 3 H), 1.96–1.92 (m, 1 H), 1.77–1.67 (m, 6 H), 1.36–1.31 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 173.4, 171.5, 170.8, 170.0, 169.7, 164.9, 133.5, 129.9 (2 CH_Ph), 128.8, 128.6 (2 CH_Ph), 81.8, 78.5, 73.7, 72.9, 70.3, 68.4, 61.8, 33.4, 30.5, 25.2, 21.7, 21.4, 20.9, 20.8, 20.7, 20.4.

MS (ESI): m/z [M + H]⁺ calcd for C₂₈H₃₅NO₁₂: 578.22; found: 578.30.

(2R,3S,4R,5R)-2-{[2-(Naphthalen-1-yl)imidazo[1,2-a]pyridin-3-yl]amino}tetrahydro-2H-pyran-3,4,5-triyl Triacetate (14)

A solution of 2-aminopyridine (0.5 mmol), 1-naphthaldehyde (0.5 mmol), isocyanide 9b (0.5 mmol), and ZrCl₄ (20 mol%) in MeOH (1 mL) was irradiated in a microwave oven at 100 °C for 30 min. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2), to afford 14 as a yellow oil; yield: 132 mg (51%); R_f = 0.15 (EtOAc–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ = 8.44 (d, J = 10 Hz, 1 H), 7.94 (d, J = 10 Hz, 1 H), 7.89 (d, J = 5 Hz, 2 H), 7.61–7.59 (m, 1 H), 7.49–7.43 (m, 4 H), 7.23 (t, J = 5 Hz, 1 H), 6.86 (t, J = 5 Hz, 1 H), 5.18 (br s, 1 H), 5.11 (t, J = 10 Hz, 1 H), 4.89 (dd, J = 10, 5 Hz, 1 H), 4.07–4.00 (m, 2 H), 3.77 (dd, J = 5, 0.5 Hz, 1 H), 3.32 (d, J = 15 Hz, 1 H), 2.15 (s, 3 H), 2.04 (s, 3 H), 1.94 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 171.1, 170.4, 170.0, 142.3, 138.6, 133.9, 132.7, 131.8, 128,6, 128.5, 128.3, 126.6, 126.5, 126.0, 125.3, 124.6, 123.9, 123.8, 117.8, 112.1, 90.8, 70.9, 69.0, 68.4, 65.0, 21.2, 20.8, 20.4.

MS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₇N₃O₇: 518.18; found: 518.25.

(2R,3S,4R,5R)-2-(5-Aminomethyl-1H-tetrazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (15)

A solution of paraformaldehyde (0.5 mmol), 28% aq NH₄OH (0.5 mmol), and isocyanide 9b (0.5 mmol) in MeOH (1 mL) was irradiated in a microwave oven at 100 °C for 30 min. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2) to afford 15 as a yellow oil; 86 mg (48%); R_f = 0.10 (EtOAc–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ = 5.95 (d, J = 10 Hz, 1 H), 5.76 (t, J = 10 Hz, 1 H), 5.45 (br s, 1 H), 5.26 (dd, J = 5, 0.5 Hz, 1 H), 4.39 (dd, J = 20, 15 Hz, 2 H), 4.20 (dd, J = 5, 0.5 Hz, 1 H), 3.98 (d, J = 10 Hz, 1 H), 2.23 (s, 3 H), 2.05 (s, 3 H), 1.90 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 170.3, 170.1, 169.2, 154.3, 85.7, 70.4, 67.7, 67.6 (2 CH), 41.9, 21.1, 20.8, 20.4.

MS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₉N₅O₇: 358.13; found: 358.27.

(2R,3S,4R,5R)-2-{2-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy-2-oxo­ethyl)amino]acetamido}tetrahydro-2H-pyran-3,4,5-triyl Triacetate (16)

A solution of glycine (0.5 mmol), piperonal (0.5 mmol), and isocyanide 9b (0.5 mmol) in MeOH (1 mL) was irradiated in a microwave oven at 100 °C for 30 min. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2), to afford 16 as a yellow oil; 92 mg (35%); R_f = 0.12 (EtOAc–PE, 1:1); mixture of diastereomers (dr 3:1).

¹H NMR (500 MHz, CDCl₃): δ = 6.87–6.82 (m, 2 H), 6.78–6.75 (m, 1 H), 5.94 (s, 3 H), 5.34–5.33 (m, 2 H), 5.24–5.17 (m, 2 H), 5.15–5.11 (m, 3 H), 5.09–5.05 (m, 1 H), 4.19 (s, 3 H), 4.01–3.95 (m, 2 H), 3.80–3.75 (m, 2 H), 3.73 (s, 3 H), 3.42 (dd, J = 30, 15 Hz, 2 H), 2.15 (s, 3 H), 2.08 (s, 3 H), 2.02 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 172.8, 171.6, 170.4, 170.0, 161.2 (3 CH), 131.8, 121.3, 108.7, 107.4, 101.4, 77.7, 70.7, 68.6, 68.3, 66.9, 66.3, 52.3, 48.9, 21.1, 21.0, 20.8.

MS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₈N₂O₁₂: 525.16; found: 525.28.

(2R,3S,4R,5R)-2-{1-Benzyl-4-[(2-chlorobenzoyl)oxy]piperidine-4-carboxamido}tetrahydro-2H-pyran-3,4,5-triyl Triacetate (17)

A solution of 1-benzylpiperidin-4-one (0.5 mmol), 2-chlorobenzoic acid (0.5 mmol), and isocyanide 9b (0.5 mmol) in MeCN (1 mL) was irradiated in a microwave oven at 100 °C for 30 min. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, PE–EtOAc, 1:2), to afford 17 as a yellow oil; yield: 123 mg (39%); R_f = 0.16 (EtOAc–PE, 1:1).

¹H NMR (500 MHz, CDCl₃): δ = 7.90 (d, J = 5 Hz, 1 H), 7.48–7.47 (m, 2 H), 7.36–7.29 (m, 5 H), 7.29–7.26 (m, 1 H), 5.32 (s, 1 H), 5.13 (d, J = 0.5 Hz, 1 H), 3.99 (dd, J = 5, 0.5 Hz, 1 H), 3.77 (d, J = 10 Hz, 1 H), 3.70 (br s, 1 H), 3.63 (s, 2 H), 2.91–2.89 (m, 2 H), 2.51–2.49 (m, 2 H), 2.35–2.28 (m, 4 H), 2.13 (s, 3 H), 2.00 (s, 3 H), 1.99 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 172.1, 172.0, 170.3, 169.9, 164.2, 136.8, 134.0, 133.3, 132.3, 131.4, 130.4, 130.0 (2 CH_Ph), 129.6, 128.6 (2 CH_Ph), 127.7, 126.9, 126.6, 80.4, 79.2, 70.8, 68.4, 66.1, 63.9, 62.4, 31.6, 31.4, 21.1, 20.9, 20.8.

MS (ESI): m/z [M + H]⁺ calcd for C₃₁H₃₅ClN₂O₁₀: 631.20; found: 631.40.

Acknowledgment

The work was financially supported from the NIH (1R21GM087617, 1R01GM097082, and 1P41GM094055) and by Innovative Medicines Initiative (grant agreement no: 115489).

• References

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• References

• 1 Rai VK, Singh S, Singh P, Yadav LD. S. Synthesis 2010; 4051
  Thieme Connect
• 2 Zhang F, Xi Y, Lu Y, Wang L, Liu L, Li J, Zhao Y. Chem. Commun. 2014; 50: 5771
  CrossrefPubMedSearch in Google Scholar
• 3 Bellucci MC, Terraneo G, Volonterio A. Org. Biomol. Chem. 2013; 11: 2421
  CrossrefPubMedSearch in Google Scholar
• 4 Nourisefat M, Panahi F, Khalafi-Nezhad A. Org. Biomol. Chem. 2014; 12: 9419
  CrossrefSearch in Google Scholar
• 5 Cholongitas E, Papatheodoridis GV. Ann. Gastroenterol. 2014; 27: 331 ; http://www.annalsgastro.gr/index.php/annalsgastro/index
  Search in Google Scholar
• 6 Zhang W, Kim D, Philip E, Miyan Z, Barykina I, Schmidt B, Stein H. Clin. Drug Invest. 2013; 33: 263
  CrossrefSearch in Google Scholar
• 7 Mifamurtide: A review of its use in the treatment of osteosarcoma: Frampton JE. Pediatr. Drugs 2010; 12: 141
  CrossrefSearch in Google Scholar
• 8 Dömling A. Chem. Rev. 2006; 106: 17
  CrossrefPubMedSearch in Google Scholar
• 9 Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
  CrossrefPubMedSearch in Google Scholar
• 10 Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
  CrossrefPubMedSearch in Google Scholar
• 11 Ziegler T, Kaisers HJ, Schlömer R, Koch C. Tetrahedron 1999; 55: 8397
  CrossrefSearch in Google Scholar
• 12 Ziegler T, Schlömer R, Koch C. Tetrahedron Lett. 1998; 39: 5957
  CrossrefSearch in Google Scholar
• 13 Martin-Lomas M, Chacón-Fuertes M. Carbohydr. Res. 1977; 59: 604
  CrossrefSearch in Google Scholar
• 14 Nolte RJ. M, Van Zomeren JA. J, Zwikker JW. J. Org. Chem. 1978; 43: 1978
  Search in Google Scholar
• 15 Drew KN, Gross PH. J. Org. Chem. 1991; 56: 509
  CrossrefSearch in Google Scholar
• 16 Boullanger P, Descotes G. Tetrahedron Lett. 1976; 17: 3427
  CrossrefSearch in Google Scholar
• 17 Prosperi D, Ronchi S, Panza L, Rencurosi A, Russo G. Synlett 2004; 1529
  Thieme Connect
• 18 Prosperi D, Ronchi S, Lay L, Rencurosi A, Russo G. Eur. J. Org. Chem. 2004; 395
• 19 Li X, Danishefsky SJ. J. Am. Chem. Soc. 2008; 130: 5446
  CrossrefPubMedSearch in Google Scholar
• 20 Ichikawa Y, Nishiyama T, Isobe M. J. Org. Chem. 2001; 66: 4200
  CrossrefSearch in Google Scholar
• 21 Ichikawa Y, Minami T, Kusaba S, Saeki N, Tonegawa Y, Tomita Y, Nakano K, Kotsuki H, Masuda T. Org. Biomol. Chem. 2014; 12: 3924
  CrossrefSearch in Google Scholar
• 22 Ichikawa Y, Ohara F, Kotsuki H, Nakano K. Org. Lett. 2006; 8: 5009
  CrossrefPubMedSearch in Google Scholar
• 23 Ichikawa Y, Watanabe H, Kotsuki H, Nakano K. Eur. J. Org. Chem. 2010; 6331
• 24 Neochoritis CG, Stotani S, Mishra B, Dömling A. Org. Lett. 2015; 17: 2002
  CrossrefPubMedSearch in Google Scholar
• 25 Neochoritis CG, Dömling A. Org. Biomol. Chem. 2014; 12: 1649
  CrossrefSearch in Google Scholar
• 26 Avalos M, Babiano R, Carretero MJ, Cintas P, Higes FJ, Jiménez JL, Palacios JC. Tetrahedron 1998; 54: 615
  CrossrefSearch in Google Scholar
• 27 Sudibya HG, Ma J, Dong X, Ng S, Li LJ, Liu XW, Chen P. Angew. Chem. Int. Ed. 2009; 48: 2723
  CrossrefSearch in Google Scholar