University of Groningen
Regioselective modification of carbohydrates for their application as building blocks in
synthesis
Zhang, Ji
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Publication date: 2019
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Zhang, J. (2019). Regioselective modification of carbohydrates for their application as building blocks in synthesis. Rijksuniversiteit Groningen.
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Chapter 3
Leuckart–Wallach Approach to Sugar
Isocyanides and Its application in
Isocyanide-Based Multicomponent
Reactions
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.
3.1 Introduction
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.1–4 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).
Figure 1. Recently approved drugs containing sugar moieties.
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 is based
on the unusual reactivity of isocyanides, the so-called 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 bromides13–16 mostly using CN-,
from the glycosyl isothiocyanate17 via reduction or via the classically and most
commonly using the Ugi approach (NH2 → NHCHO → NC) from the anomeric
Mechanism of the “Leuckart-Wallach” approach to a sugar formamide
Scheme 1. A Leuckart–Wallach approach to sugar isocyanides
These methods either give complex mixtures (with AgCN), use harsh conditions (boiling xylene), expensive materials, limited applications, and lengthy syntheses (four to six 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 (We
realized this is not a real Leuckart–Wallach reaction. In the last step of the Leuckart–Wallach reaction, the iminium ion intermediate is reduced by formic acid, but in the last step of our mechanism this is not the case. Rather, the iminium ion intermediate was attacked by a hydroxyl to form a six membered ring. The mechanism of this ring closing reaction is depicted in scheme 1). Moreover, we exemplify the unprecedented use of arabinosyl and glucosyl isocyanides in six different IMCRs.
3.2 Results and discussion
We envisaged the use of the Leuckart–Wallach reaction on two basic and quite representative sugars, D-glucose and D-arabinose respectively. After the per-O-acetylation followed by exclusive deprotection of the anomeric hydroxyl group, we performed the aforementioned reaction using both microwave and by conventional heating (Scheme 2).24 Interestingly, we obtained the corresponding
formamides 6 and 7 in moderate to good yields. Typical dehydration of 6 and 7 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 of 6 with Z-configuration18,26 (X ray
structure see Fig 2), which could be converted into 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 formamide with cis and trans conformation. We speculate that the selective
cis-6-β-anomer formation is caused by the formation of a preferred hydrogen
bonding of the formamide NH with a neighboring acetyl group. On the other hand formamide 7 was formed as a complex anomeric mixture. After dehydration of 7 the arabinosyl isocyanide was obtained as a mixture of anomers (9a/9b, 1:2) in 72% overall yield. Subsequently, the anomers were separated by column chromatography.
Figure 2. X-ray structure of 6
Having established the synthesis of 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 glucosyl isocyanide 8 was successfully utilized in the Ugi four-component (U-4CR) Ugi tetrazole (UT-4CR), Ugi β-lactam (UBL-3CR), and Passerini three-component (P-3CR) reactions yielding compounds 10–13 (Scheme 3). The reactions proceeded at room temperature or under microwave irradiation at 100°C giving good to excellent yields without epimerization on the α-carbon of the isocyanide.
Scheme 3. Four different types of multicomponent reactions with glycosyl isocyanide 8.
After these successful efforts, we decided to investigate the arabinosyl isocyanide (Scheme 4). We selected the separated β-anomer 9b and we performed a Passerini three-component reaction (P-3CR), Ugi tetrazole variation bearing a free amino group (UT-4CR’), a Gröbcke–Blackburn–Bienaymé reaction (GBB-3CR), finally a Ugi five-center four-component reaction (U-5C-4CR) yielding compounds 14–17. It seems that isocyanide 9b is less reactive than 8, so only under microwave conditions we were able to obtain the desired products in acceptable yields. In both cases we wanted to employ drug like 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.
Scheme 4. Four different types of multicomponent reactions with arabinosyl isocyanide 9b.
3.3 Conclusion
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.
3.4 Experimental Section
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®
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 SFCMS instrument.
2,3,4,6-Tetra-O-acetyl-D-glucopyranose (4)27
To a stirred solution of 1,2,3,4,6-penta-O-acetyl-α-D
-glucopyranose (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, after which the solvent were removed in vacuo and the residue was purified by column chromatography to afford 4 as an oil; yield: 940 mg (90%); Rf = 0.49 (EtOAc–PE, 1:1). 1H NMR (500
MHz, CDCl3): δ (mixture of anomers, α/β, 3:1) δ (α-anomer) = 5.53 (t, J = 9.8 Hz,
1H), 5.46 (d, J = 3.7 Hz, 1H), 5.08 (t, J = 9.6 Hz, 1H), 4.90 (dd, J = 10.3, 3.6 Hz, 1H), 4.29 – 4.20 (m, 2H), 4.16 – 4.10 (m, 1H), 3.37 (br s, 1H), 2.09 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H).
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%); Rf = 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
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 allowed to cool down to r.t. and extracted with CH2Cl2 (3 × 30 mL). The combined organic
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%); Rf = 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), 5.35-5.29 (m, 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, 20.80, 20.75. 2,3,4-Tri-O-acetyl-N-formyl-D-glucopyranosylamine (7)
Following the same procedure as for 6, compound 7 was synthesized from 5 as transparent crystals; yield: 376 mg (62%); Rf = 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
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 an aqueous solution of saturated 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%); Rf = 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%); (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%);
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, 20.64, 20.61. β-Anomer 9b
Yellow solid; yield: 410 mg (48%);
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%); Rf = 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.
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%); Rf = 0.25 (EtOAc–PE, 1:1); mixture of diastereomers (dr 1:0.8). 1H NMR (500 MHz, CDCl3): δ = 7.35 – 7.30 (m, 4H), 7.26 – 7.17 (m, 9H), 7.16-7.14 (m, 4H), 6.08 (d, J = 9.5 Hz, 1H), 6.03 (d, J = 9.5 Hz, 1H), 5.90 (t, J = 9.3 Hz, 1H), 5.73 (t, J = 9.3 Hz, 1H), 5.43 (s, 1H), 5.36 (s, 1H), 5.30-5.15 (m, 4H), 4.19 – 4.08 (m, 3H), 3.95 (dd, J = 12.6, 2.0 Hz, 1H), 3.79 (dd, J = 12.6, 2.1 Hz, 1H), 3.58 (ddd, J = 9.8, 4.1, 2.3 Hz, 2H), 3.53 (ddd, J = 9.8, 4.6, 2.1 Hz, 1H), 2.95 – 2.80 (m, 8H), 2.34 (s, 3H), 2.33 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.77 (s, 3H), 1.64 (s, 3H).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 CHPh), 128.8 (4 CHAr), 127.0 (2 CHPh), 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 C31H38N5O9:
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%); Rf = 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 C25H30BrN2O11: 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%); Rf = 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 CHPh), 128.8, 128.6 (2 CHPh), 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 C28H36NO12: 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%); Rf = 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), TMSN3 (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%); Rf = 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%); Rf = 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, 3H), 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: 525.17; 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%); Rf = 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 CHPh), 129.6, 128.6 (2 CHPh), 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: 631.21; found: 631.40.
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