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DOI: 10.1055/a-1709-3305
Hirao Cross-Coupling Reaction as an Efficient Tool to Build Non-natural C2-Phosphonylated Sugars
M.M. and A.F. thank the Fondation de la Maison de la Chimie for financial support.
Abstract
A range of C2-phosphonylated sugars have been accessed through a palladium-catalyzed Hirao cross-coupling on 2-iodoglycals using trialkylphosphites as phosphorylating reagents. The developed conditions led to the creation of an unnatural C–P bond on sugars and proved to be compatible with diversely protected glycals (acetyl-, benzyl-, PMB-protected) as well as with unprotected substrates. Several monosaccharides and one disaccharide have been synthesized by applying this methodology. Deprotection conditions are also described.
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The incorporation of a phosphorus-containing function on biomolecules (generally a phosphate in Nature) appears to be a crucial tool for the biological machinery. In cells, these reactions are carried out by two types of proteins; namely, the kinase and the phosphotransferase proteins.[1] Indeed, the addition of a highly water-soluble phosphate function allows the possibility to modulate the properties or the role of a molecule.[2] In particular, phosphorylation reactions of sugars occur at many cellular stages and their roles are very diverse.[3] For instance, the phosphorylation of glycosides on their alcohol functions plays a key role in their catabolism, since it prevents their cell efflux. Another well-known example of a crucial phosphorylated glycoside is the adenosine triphosphate molecule (ATP), which is involved in cellular energy storage and synthesized through the phosphorylation of the adenosine diphosphate. Depending on the enzyme, the site where the phosphorylation occurs on sugar can be various. In most cases, this process takes place at the more reactive primary alcohol function but phosphorylation of secondary sites or of the anomeric position is also known.[4] With a therapeutic objective, the synthesis of these phosphorylated bioactive compounds as well as their non-natural mimics, possessing a better biological activity or a better pharmacokinetic profile, attracted the attention of the chemist community. The design of unnatural biomolecule analogues is generally based on replacing a natural link with a non-natural one. For example, C-branched glycosides include stable carbon–carbon (C–C) bonds instead of the natural carbon-oxygen (C–O) or carbon–nitrogen (C–N) bonds.[5] Moreover, the glycochemist toolbox has grown significantly in recent decades and provided elegant ways to build non-natural glycosidic bonds. While the literature focuses on the anomeric position, the development of an efficient synthesis of the bench-stable 2-iodoglycal building blocks by Vankar et al. in 2014,[6] paved the way for a wide diversity of C2-glyco-analogues through the use of metal-catalyzed cross-couplings. Standard cross-coupling reactivities such as Suzuki–Miyaura, Sonogashira or Heck reactions have been successfully applied on these scaffolds in addition to several examples of carbonylative processes.[7] Despite the strong interest in developing such reactivity on 2-iodoglycals in recent years, the large majority of the examples have focused on the formation of C–C bonds. Indeed, only two publications deal with the creation of carbon–heteroatom bonds on these substrates. The first example, presented by Messaoudi et al. in 2017, concerns the formation of the C–S bond via a palladium-catalyzed thiolation reaction (Scheme [1]).[8] The second example was described very recently by our group, enlarging this field by developing a dual nickel/copper catalysis for the C–N bond formation on diverse 2-iodoglycals leading to glycosamine analogues (Scheme [1]).[9]
We were interested in achieving non-natural C2-phosphonylated glycosides by using a palladium-catalyzed Hirao cross-coupling reactivity[10] on 2-iodoglycals (Scheme [1]). These targeted mimics will bear a non-natural C–P bond on position 2, which will open up access to original glyco-analogues.
The investigation of the Hirao reactivity on 2-iodoglycals was performed on compound 1a (Table [1]), obtained by iodination of the commercial 3,4,6-tri-OAc-d-glucal according to Vankar’s conditions.[6] Compound 1a was reacted with a small excess of diethylphosphite in the presence of Pd(OAc)2 as the catalyst, XPhos as the ligand, and DIPEA as the base in a mixture of tBuOH/EtOH at 110 °C overnight (entry 1). These initial conditions allowed the desired product 2a to be formed in a low yield of 21% (1H NMR analysis). Evidence for the palladium-catalyzed mechanism of this reaction was obtained from a control experiment in which the palladium source and the ligand were absent, which led to the complete recovery of the starting material (entry 2). The use of each co-solvent as unique medium led to a drastic reduction of the yield (entries 3 and 4). However, a decrease of the reaction temperature to 70 °C led to an increase in the 1H NMR yield (entry 5). Further improvements were obtained by reducing the ligand amount and by replacing the tBuOH co-solvent with DMF, which furnished a good 64% yield (entries 6 and 7).
a Reaction conditions: 1a (0.113 mmol, 1 equiv), [Pd] (10 mol%), ligand (x mol%), DIPEA (3 equiv), diethylphosphite (1.5 equiv), solvent, at T °C during the indicating time under argon.
b Yields were determined by 1H NMR analysis using HMPA (1 equiv) as internal reference.
c The reaction was performed under air.
d Triethylphosphite was used as partner.
e 70% isolated.
The use of other polar co-solvents (Table [1], entries 8 and 9), other phosphorylated ligands (entries 11–13), or other palladium complexes (entries 14 and 15) failed to improve the yield of 2a. Moreover, the inert atmosphere proved to be crucial, since the reaction conducted under air furnished 2a in only 36% yield (entry 10). Diethylphosphite is in equilibrium between the P(V) and the P(III) forms. This equilibrium is largely in favor of the P(V) species. According to the literature,[11] the P(III) oxidation state of the phosphorylated reagent is assumed to be the reactive form in this transformation. Therefore, a P(III) reagent, the triethylphosphite was tested (entry 16). The use of this latter compound increased considerably the yield in 2a (90% by 1H NMR and 70% isolated) and enhanced the reactivity drastically (1 h of reaction time instead of 16 h with the diethylphosphite). According to literature,[11] the mechanism is supposed to proceed first through the oxidative addition of a palladium(0) complex into the carbon–iodide bond of 1 (intermediate I, Scheme [2]). Then, a ligand exchange with the nucleophilic triethylphosphite forms the phosphonium ion II. An Arbusov reaction, mediated by a basic species in the medium, leads to the removal of an ethyl group and to the formation of a P(V)-phosphonate function III. Finally, a reductive elimination forms the desired product 2 and regenerates the catalyst. The compatibility of the optimized conditions (Table [1], entry 16) was then explored with different 2-iodoglycals as well as diverse trialkylphosphites (Scheme [3]). Satisfyingly, these conditions proved to tolerate benzyl-protected glycals (on the condition of increasing the reaction temperature) (2b) as well as PMB-protected- (2d) or even unprotected substrates (2c) in high yields in all cases. Moreover, the glycal configuration does not affect the reactivity, since d-glucal- (2a–d), d-galactal- (2e and 2f), d-lactal- (a disaccharide) (2h) or l-rhamnal-configurations (2g) were successful in this transformation, with yields always greater than 50%. In terms of trialkylphosphite reagents, the use of ethanol as solvent led to transesterification issues when other trialkylphosphites were used.
Indeed, a mixture of inseparable phosphonylated compounds was obtained in this case. To avoid this drawback, the nature of the protic co-solvent has to be suitable for the chosen trialkylphosphite. Therefore, trimethylphosphite was coupled with 1a using a mixture of DMF/MeOH (Scheme [3,] 2i) as medium and DMF/iPrOH was used with triisopropylphosphite (2j). In both cases, the corresponding phosphonylated compound was obtained in good to excellent yield.
The deprotection of the obtained molecules is a fundamental requirement in glycochemistry and enhances the biological relevance of the structures (Scheme [4]). The deprotection of the sugar hydroxyl groups was thus investigated. Acetyl protecting groups could be removed on 2a by using classical Zemplen conditions, leading to compound 2c in excellent yield. Moreover, benzyl groups of 2b could be cleaved by hydrogenolysis in the presence of palladium catalyst, furnishing 2c in good yield.
To conclude, access to glyco-analogues possessing an unnatural C–P bond in position 2 has been developed by using a palladium-catalyzed Hirao cross-coupling reaction on 2-iodoglycals. The use of a reactive P(III)-phosphorylated reagent permitted high yields to be reached in low reaction times. Several standard sugar protecting groups (acetyl, benzyl, PMB) were shown to be successfully employed under the developed conditions, as well as unprotected 2-iodoglycals. A disaccharide example was also described. Ten examples with yields between 56 and 91% were synthesized by using this approach. The deprotection of two obtained examples led to original glyco-analogues with potential biological interest. The biological evaluation of these structures is under investigation.
All chemical operations were carried out using standard screw-sealed tubes. Acetonitrile was purified before use by distillation under an argon atmosphere. Other solvents were used without further purification. The ‘cHex’ abbreviation will be used to name cyclohexane. Commercially available chemicals were used as received unless otherwise stated. Reactions were monitored by thin-layer chromatography on silica gel plates (60 F254 aluminum sheets) which were rendered visible by ultraviolet and/or by spraying with vanillin (15%) + sulfuric acid (2.5%) in EtOH followed by heating. 1H NMR (400 MHz), 13C NMR (100.5 MHz), and 31P NMR (162 MHz) were recorded with a Bruker Avance NEO 400 MHz spectrometer at 298 K unless otherwise stated. Chemical shifts are given in ppm (δ) and are referenced to the internal solvent signal or to TMS used as an internal standard. Multiplicities are declared as: s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quadruplet), dd (doublet of doublet), ddd (doublet of doublet of doublet), dt (doublet of triplet), m (multiplet). Coupling constants J are given in Hz. Infrared spectra (IR) were recorded with a Bruker Tensor 27 with a FTIR system using a diamond window Dura SamplIR II, and the data are reported in reciprocal centimeters (cm–1) in the range 4000–600 cm–1. Optical rotations were measured with an Anton Paar MCP 200 polarimeter at 589 nm. [α] is expressed in deg·cm3·g–1·dm–1, and c is expressed in g/100 cm3. HRMS were determined with a QTOF mass analyzer coupled with electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) with a resolution of 12000.
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Starting Substrates
Compounds 2-iodo-3,4,6-tri-O-acetyl-d-glucal, 2-iodo-3,4,6-tri-O-benzyl-d-glucal, 2-iodo-3,4,6-tri-O-benzyl-d-galactal, 2-iodo-3,4-di-O-acetyl-l-rhamnal, 2-iodo-3,6-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-d-glucal were prepared according to the literature:[6] [7m] the corresponding glycal was dissolved in anhydrous acetonitrile (8 mL/mmol) under argon, and the resulting mixture was heated to 80 °C. At this temperature, N-iodosuccinimide (1.2 equiv) and silver nitrate (20 mol %) were added. The resulting mixture was stirred at 80 °C for 1–2 h. The mixture was filtrated on Celite with EtOAc, and concentrated with silica. The obtained crude material was purified on silica gel to furnish the corresponding 2-iodoglycal.
Compounds 2-iodo-d-glucal and 2-iodo-d-galactal were obtained by following the same iodination procedure, followed by deprotection of the acetyl groups under basic conditions according to the literature.[7m]
Compound 3,4,6-tri-O-para-methoxybenzyl-d-glucal was obtained by following a reported procedure.[12]
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2-Iodo-3,4,6-tri-O-para-methoxybenzyl-d-glucal
2-Iodo-3,4,6-tri-O-para-methoxybenzyl-d-glucal was prepared by following the literature procedure:[6] 3,4,6-Tri-O-para-methoxybenzyl-d-glucal (2.236 g, 1 equiv, 4.41 mmol) was dissolved in anhydrous acetonitrile (35 mL) under argon, and the resulting mixture was heated to 80 °C. At this temperature, N-iodosuccinimide (1.192 g, 1.2 equiv, 5.30 mmol) and silver nitrate (150 mg, 0.2 equiv, 0.88 mmol) were added, and the resulting mixture was stirred at 80 °C for 2 h. The mixture was filtrated on Celite with EtOAc, and concentrated with silica. The obtained crude material was purified on silica gel (toluene/EtOAc, 95:5) to furnish the corresponding 2-iodo-3,4,6-tri-O-para-methoxybenzyl-d-glucal.
Yield: 1.125 g (1.78 mmol, 40%); colorless oil; [α] d 20 +8.7 (c = 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 8.5 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.16 (d, J = 8.5 Hz, 2 H), 6.88–6.85 (m, 6 H), 6.71 (s, 1 H), 4.63 (d, J = 10.9 Hz, 2 H), 4.57–4.47 (m, 4 H), 4.25 (dd, J = 9.9, 6.0 Hz, 1 H), 4.04 (d, J = 5.0 Hz, 1 H), 3.93 (dd, J = 6.7, 5.2 Hz, 1 H), 3.80 (s, 9 H), 3.74 (dd, J = 10.7, 5.6 Hz, 1 H), 3.66 (dd, J = 10.7, 3.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 159.5, 159.5, 159.4, 148.4, 130.0, 129.9, 129.8, 129.7, 129.6, 114.0, 113.9, 78.8, 76.8, 73.8, 73.2, 72.9, 72.1, 70.8, 67.6, 55.4, 55.4.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C30H33INaO7 +: 655.1169; found: 655.1162.
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General Procedures
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Phosphonylation Reaction to give 2; General Procedure
In a sealed tube were added Pd(OAc)2 (10 mol%), XPhos (30 mol%), and 1a (1 equiv), and the reaction vessel was placed under argon atmosphere. A mixture of DMF/ROH (1:1), DIPEA (3 equiv) and the trialkylphosphite (1.5 equiv) were added to the mixture under argon. The resulting mixture was stirred for the indicating time and temperature. The mixture was filtered on Celite with EtOAc, and then concentrated under vacuum. The crude material was finally purified on silica gel using the indicated solvent.
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1H NMR Yield Determination; General Procedure
The NMR yield of 2a was determined with HMPA as internal reference: HMPA (1 equiv compared to 1a) was added after filtration and concentration of the crude material. The NMR yield of 2a based on the 1H NMR and the 31P NMR spectra could be determined by integration of the following analytical signals: (1) 1H NMR signals at 2.57 ppm (CH3 of HMPA – calibrated for 18 H) compared with the integrations of product signal: d at 7.31 ppm (pseudo-anomeric CH of product 2a). (2) 31P NMR signals at +25.5 ppm (P of HMPA – calibrated for 1 P) compared with the integrations of product signal: s at +17.5 ppm (P of product 2a). The reaction yield was determined from the mean value of these integrations.
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2-(Diethylphosphonate)-3,4,6-tri-O-acetyl-d-glucal (2a)
Compound 2a was obtained by following the general procedure for phosphonylation, using Pd(OAc)2 (2.2 mg, 10 mol%, 0.01 mmol), XPhos (14.3 mg, 30 mol%, 0.03 mmol), 1a (40 mg, 1 equiv, 0.1 mmol), DIPEA (52.2 μL, 3 equiv, 0.3 mmol), triethylphosphite (25.7 μL, 1.5 equiv, 0.15 mmol), and DMF/EtOH (0.4 mL, 1:1), and the resulting mixture was stirred for 1 h at 70 °C. Compound 2a was obtained after purification on silica gel (cHex/EtOAc, 1:1 then 2:8 then 0:100).
Yield: 28.0 mg (0.070 mmol, 70%); yellowish oil; [α] d 20 +8.9 (c 1.14, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 10.2 Hz, 1 H), 5.54–5.49 (m, 1 H), 5.14–5.09 (m, 1 H), 4.52–4.33 (m, 2 H), 4.16 (dd, J = 11.7, 3.5 Hz, 1 H), 4.10–3.97 (m, 4 H), 2.07 (s, 3 H), 2.04 (s, 3 H), 2.02 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 169.5, 169.5, 157.4 (d, J = 22.9 Hz), 98.71 (d, J = 201.2 Hz), 74.6, 66.2 (d, J = 9.7 Hz), 63.4 (d, J = 3.7 Hz), 62.1 (d, J = 5.4 Hz), 62.0 (d, J = 5.2 Hz), 61.1, 21.0, 20.9, 20.8, 16.5 (d, J = 4.2 Hz), 16.4 (d, J = 3.6 Hz).
31P NMR (162 MHz, CDCl3): δ = 17.5.
IR: 3460, 2984, 1742, 1620, 1367, 1215, 1184, 1016, 958, 794 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd for C16H25O10NaP+: 431.1083; found: 431.1079.
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2-(Diethylphosphonate)-3,4,6-tri-O-benzyl-d-glucal (2b)
Compound 2b was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (2.2 mg, 10 mol%, 0.01 mmol), XPhos (14.3 mg, 30 mol%, 0.03 mmol), 2-iodo-3,4,6-tri-O-benzyl-d-glucal (54 mg, 1 equiv, 0.1 mmol), DIPEA (52.2 μL, 3 equiv, 0.3 mmol), triethylphosphite (25.7 μL, 1.5 equiv, 0.15 mmol) and DMF/EtOH (0.4 mL, 1:1), and the resulting mixture was stirred for 1 h at 110 °C. Compound 2b was obtained after purification on silica gel (cHex/EtOAc, 8:2 then 7:3 then 1:1).
Yield: 40.0 mg (0.075 mmol, 75 %); yellowish oil; [α] d 20 –1.5 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.31–7.19 (m, 16 H), 4.62 (d, J = 11.1 Hz, 1 H), 4.55 (d, J = 11.8 Hz, 1 H), 4.51 (d, J = 11.1 Hz, 1 H), 4.50 (d, J = 11.8 Hz, 1 H), 4.46–4.43 (m, 2 H), 4.11–3.91 (m, 6 H), 3.81 (dd, J= 3.6, 7.2 Hz, 1 H), 3.75 (dd, J = 10.6, 6.8 Hz, 1 H), 3.62 (dd, J = 10.6, 4.6 Hz, 1 H), 1.21 (t, J = 7.1 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 156.4 (d, J = 23.1 Hz), 138.1, 137.9, 137.7, 128.7, 128.6, 128.5, 128.1, 128.1, 127.9, 127.9, 99.6 (d, J = 197.0 Hz), 76.9, 73.5, 72.8, 72.3, 72.0 (d, J = 9.8 Hz), 70.7 (d, J = 3.8 Hz), 68.0, 61.8 (d, J = 4.8 Hz), 61.7 (d, J = 5.0 Hz), 16.4 (d, J = 5.4 Hz), 16.3 (d, J = 5.9 Hz).
31P NMR (162 MHz, CDCl3): δ = 21.6.
IR: 2981, 1722, 1620, 1452, 1192, 1093, 1022, 970, 750, 698 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C31H37O7NaP+: 575.2175; found: 575.2172.
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2-(Diethylphosphonate)-d-glucal (2c)
Compound 2c was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (2.2 mg, 8 mol%, 0.01 mmol), XPhos (14.3 mg, 23 mol%, 0.03 mmol), 2-iodo-d-glucal (36.7 mg, 1 equiv, 0.135 mmol), DIPEA (52.2 μL, 2.3 equiv, 0.3 mmol), triethylphosphite (25.7 μL, 1.15 equiv, 0.15 mmol) and DMF/EtOH (0.4 mL, 1:1), and the resulting mixture was stirred for 1 h at 70 °C. Compound 2c was obtained after purification on silica gel (CH2Cl2/MeOH, 9:1 then 8:2)
Yield: 29.0 mg (0.103 mmol, 76 %); colorless oil; [α] d 20 +35.8 (c 0.17, MeOH).
1H NMR (400 MHz, MeOD): δ = 7.15 (d, J = 10.4 Hz, 1 H), 4.14–4.06 (m, 6 H), 3.90–3.84 (m, 2 H), 3.82–3.78 (m, 1 H), 1.33 (t, J = 7.1 Hz, 6 H).
13C NMR (101 MHz, MeOD): δ = 157.7 (d, J = 22.9 Hz), 102.3 (d, J = 198.8 Hz), 82.0, 69.7 (d, J = 10.9 Hz), 66.9 (d, J = 2.9 Hz), 63.4 (d, J = 5.5 Hz), 63.4 (d, J = 5.2 Hz), 56.0, 16.8 (d, J = 3.5 Hz), 16.7 (d, J = 3.6 Hz).
31P (162 MHz, MeOD): δ = +22.0.
IR: 3323, 2985, 2360, 2341, 1618, 1188, 1024, 972, 796, 679 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C10H19NaO7P+: 305.0761; found: 305.0767.
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2-(Diethylphosphonate)-3,4,6-tri-O-paramethoxybenzyl-d-glucal (2d)
Compound 2d was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (1.5 mg, 10 mol%, 0.0075 mmol), XPhos (10.7 mg, 30 mol%, 0.022 mmol), 2-iodo-3,4,6-tri-O-para-methoxybenzyl-d-glucal (48.0 mg, 1 equiv, 0.075 mmol), DIPEA (39.0 μL, 3 equiv, 0.22 mmol), triethylphosphite (16.0 μL, 1.5 equiv, 0.11 mmol) and DMF/EtOH (0.6 mL, 1:1), and the resulting mixture was stirred for 1 h at 90 °C. Compound 2d was obtained after purification on silica gel (cHex/EtOAc, 8:2).
Yield: 38.2 mg (0.06 mmol, 80%); yellowish oil; [α] d 20 –8.0 (c 0.87, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.17–7.09 (m, 7 H), 6.83–6.77 (m, 6 H), 4.56 (d, J = 10.9 Hz, 1 H), 4.48 (d, J = 11.4 Hz, 1 H), 4.45 (d, J = 10.9 Hz, 1 H), 4.42–4.34 (m, 4 H), 4.04–3.92 (m, 5 H), 3.76 (s, 9 H), 3.75–3.66 (m, 2 H), 3.56 (dd, J = 10.6, 4.3 Hz, 1 H), 1.22 (t, J = 7.0 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 159.5, 159.4, 159.3, 156.4 (d, J = 23.1 Hz), 130.4, 130.0, 129.8, 129.7, 129.6, 129.5, 114.0, 113.9, 113.8, 99.6 (d, J = 196.9 Hz), 77.1, 73.2, 72.5, 72.0, 71.7 (d, J = 9.9 Hz), 70.5 (d, J = 3.9 Hz), 67.7, 61.8 (d, J = 4.6 Hz), 61.7 (d, J = 5.0 Hz), 55.5, 55.4 (2C), 16.5 (d, J = 4.2 Hz), 16.4 (d, J = 4.4 Hz).
31P NMR (162 MHz, CDCl3): δ = 21.0.
IR: 2978, 1616, 1514, 1247, 1178, 1059, 1030, 964, 820, 765 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd for C34H43NaO10P+: 665.2486; found: 665.2489.
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2-(Diethylphosphonate)-3,4,6-tri-O-benzyl-d-galactal (2e)
Compound 2e was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (2.2 mg, 10 mol%, 0.01 mmol), XPhos (14.3 mg, 30 mol%, 0.03 mmol), 2-iodo-3,4,6-tri-O-benzyl-d-galactal (54.2 mg, 1 equiv, 0.1 mmol), DIPEA (52.2 μL, 3 equiv, 0.3 mmol), triethylphosphite (25.7 μL, 1.5 equiv, 0.15 mmol) and DMF/EtOH (0.4 mL, 1:1), and the resulting mixture was stirred for 1.75 h at 110 °C. Compound 2e was obtained after purification on silica gel (cHex/EtOAc, 8:2 then 7:3 then 1:1).
Yield: 42 mg (0.074 mmol, 74%); yellowish oil; [α] d 20 –10.0 (c 1.13, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.19 (m, 15 H), 7.06 (d, J = 10.1 Hz, 1 H), 4.76 (d, J = 11.0 Hz, 1 H), 4.72 (d, J = 11.6 Hz, 1 H), 4.69 (d, J = 11.0 Hz, 1 H), 4.58 (d, J = 11.8 Hz, 1 H), 4.51 (d, J = 11.9 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.43–4.39 (m, 1 H), 4.33–4.27 (m, 1 H), 4.17–4.05 (m, 1 H), 4.04–3.91 (m, 4 H), 3.87 (dd, J = 11.0, 8.0 Hz, 1 H), 3.77 (dd, J = 11.0, 3.6 Hz, 1 H), 1.21 (t, J = 6.8 Hz, 3 H), 1.19 (t, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 155.70 (d, J = 22.1 Hz), 138.5, 138.0, 137.9, 128.6, 128.6, 128.3, 128.1, 128.1, 128.0, 127.9, 127.7, 100.8 (d, J = 197.0 Hz), 76.6, 74.0, 73.6 (2C), 73.0, 68.0, 63.8 (d, J = 5.8 Hz), 61.8 (2C) (d, J = 5.1 Hz), 16.4 (d, J = 6.7 Hz), 16.3 (d, J = 7.1 Hz).
31P NMR (162 MHz, CDCl3): δ = 20.0.
IR: 2926, 2358, 1728, 1614, 1454, 1234, 1093, 1022, 960, 734, 696 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C31H37NaO7P+: 575.2169; found: 575.2171.
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2-(Diethylphosphonate)-d-galactal (2f)
Compound 2f was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (1.5 mg, 10 mol%, 0.073 mmol), XPhos (10.4 mg, 30 mol%, 0.022 mmol), 2-iodo-d-galactal (20 mg, 1 equiv, 0.073 mmol), DIPEA (38.0 μL, 3 equiv, 0.219 mmol), triethylphosphite (15.6 μL, 1.5 equiv, 0.109 mmol) and DMF/EtOH (0.6 mL, 1:1), and the resulting mixture was stirred for 1 h at 70 °C. Compound 2f was obtained after purification on silica gel (CH2Cl2/MeOH, 9:1).
Yield: 13 mg (0.048 mmol, 63%); as yellowish oil; [α] d 20 +32.2 (c 1.34, CHCl3).
1H NMR (400 MHz, MeOD): δ = 7.10 (d, J = 10.6 Hz, 1 H), 4.42 (t, J = 4.0 Hz, 1 H), 4.16–4.04 (m, 5 H), 4.01–3.96 (m, 1 H), 3.91 (dd, J = 11.9, 6.7 Hz, 1 H), 3.80 (dd, J = 11.9, 4.7 Hz, 1 H), 1.33 (t, J = 7.0 Hz, 6 H).
13C NMR (101 MHz, MeOD): δ = 157.9 (d, J = 22.4 Hz), 102.6 (d, J = 198.7 Hz), 80.3, 66.7 (d, J = 9.5 Hz), 64.8 (d, J = 2.4 Hz), 63.5 (d, J = 5.8 Hz), 63.4 (d, J = 5.8 Hz), 61.7, 16.8 (d, J = 4.2 Hz), 16.7 (d, J = 4.3 Hz).
31P NMR (162 MHz, MeOD): δ = 22.0.
IR: 3340, 2983, 2360, 2341, 1614, 1196, 1024, 970, 798, 759 cm–1.
HRMS (TOF ES+): m/z [M + H]+ calcd. for C10H20O7P+: 283.0947; found: 283.0955.
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2-(Diethylphosphonate)-3,4-di-O-acetyl-l-rhamnal (2g)
Compound 2g was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (2.2 mg, 10 mol%, 0.01 mmol), XPhos (15.7 mg, 30 mol%, 0.033 mmol), 2-iodo-3,4-di-O-acetyl-l-rhamnal (40 mg, 1 equiv, 0.11 mmol), DIPEA (57.3 μL, 3 equiv, 0.33 mmol), triethylphosphite (23.5 μL, 1.5 equiv, 0.165 mmol) and DMF/EtOH (0.4 mL, 1:1), and the resulting mixture was stirred for 2 h at 70 °C. Compound 2g was obtained after purification on silica gel (cHex/EtOAc, 7:3 then 6:4 then 1:1).
Yield: 39 mg (0.097 mmol, 88%); yellowish oil; [α] d 20 +21.9 (c 1.46, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 10.3 Hz, 1 H), 5.51–5.46 (m, 1 H), 4.97–4.88 (m, 1 H), 4.38–4.28 (m, 1 H), 4.08–3.95 (m, 4 H), 2.03 (s, 3 H), 2.01 (s, 3 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 169.8, 169.7, 157.9 (d, J = 22.7 Hz), 97.6 (d, J = 201.2 Hz), 73.3, 70.2 (d, J = 9.9 Hz), 64.1 (d, J = 3.6 Hz), 62.0 (d, J = 5.3 Hz), 61.8 (d, J = 5.1 Hz), 21.0, 21.0, 16.4 (d, J = 5.1 Hz), 16.4 (d, J = 5.1 Hz).
31P NMR (162 MHz, CDCl3): δ = 18.5.
IR: 2985, 2360, 1741, 1620, 1369, 1217, 1190, 1016, 964, 790 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C14H23NaO8P+: 373.1023; found: 373.1027.
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2-(Diethylphosphonate)-3,6-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-d-glucal (2h)
Compound 2h was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (1.3 mg, 10 mol%, 0.006 mmol), XPhos (8.8 mg, 30 mol%, 0.019 mmol), 2-iodo-3,6-di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-d-galacto-pyranosyl)-d-glucal (35 mg, 1 equiv, 0.051 mmol), DIPEA (32.0 μL, 3 equiv, 0.18 mmol), triethylphosphite (13.2 μL, 1.5 equiv, 0.093 mmol) and DMF/EtOH (0.8 mL, 1:1), and the resulting mixture was stirred for 1 h at 70 °C and 1 h at 80 °C. Compound 2h was obtained after purification on silica gel (CH2Cl2/MeOH, 95:5).
Yield: 20 mg (0.028 mmol, 56%); yellowish oil; [α] d 20 +2.8 (c 1.55, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 10.3 Hz, 1 H), 5.58–5.55 (m, 1 H), 5.35 (d, J = 3.2 Hz, 1 H), 5.10 (dd, J = 10.4, 7.9 Hz, 1 H), 4.97 (dd, J = 10.5, 3.4 Hz, 1 H), 4.61 (d, J = 7.9 Hz, 1 H), 4.45–4.41 (m, 1 H), 4.28 (dd, J = 12.0, 7.8 Hz, 1 H), 4.20 (dd, J = 12.1, 4.6 Hz, 1 H), 4.16–4.10 (m, 2 H), 4.10–3.97 (m, 5 H), 3.97–3.91 (m, 2 H), 2.10 (s, 3 H), 2.09 (s, 3 H), 2.02 (s, 3 H), 2.01 (s, 3 H), 2.01 (s, 3 H), 1.94 (s, 3 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.7, 170.6, 170.3, 170.2, 169.4, 169.3, 157.3 (d, J = 23.4 Hz), 101.2, 97.3 (d, J = 200.1 Hz), 74.7, 72.5 (d, J = 9.3 Hz), 71.1, 70.9, 68.8, 66.9, 63.0 (d, J = 4.4 Hz), 62.2 (d, J = 4.2 Hz), 61.8 (d, J = 4.8 Hz), 61.5, 61.0, 21.0, 20.9, 20.8, 20.8, 20.7, 20.7, 16.5 (d, J = 5.0 Hz), 16.4 (d, J = 4.5 Hz).
31P NMR (162 MHz, CDCl3): δ = 18.5.
IR: 2985, 2361, 1745, 1622, 1369, 1220, 1047, 1022, 972, 796 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C28H41NaO18P+: 719.1923; found: 719.1922.
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2-(Dimethylphosphonate)-3,4,6-tri-O-acetyl-d-glucal (2i)
Compound 2i was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (2.2 mg, 10 mol%, 0.01 mmol), XPhos (14.3 mg, 30 mol%, 0.03 mmol), 1a (40 mg, 1 equiv, 0.1 mmol), DIPEA (52.2 μL, 3 equiv, 0.3 mmol), trimethylphosphite (17.7 μL, 1.5 equiv, 0.15 mmol) and DMF/MeOH (0.4 mL, 1:1), and the resulting mixture was stirred for 1 h at 70 °C. Compound 2i was obtained after purification on silica gel (cHex/EtOAc, 1:1 then 2:8 then 0:100).
Yield: 23 mg (0.06 mmol, 60%); yellowish oil; [α] d 20 +4.9 (c 1.09, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 10.3 Hz, 1 H), 5.53–5.46 (m, 1 H), 5.15–5.11 (m, 1 H), 4.49–4.45 (m, 1 H), 4.42 (dd, J= 11.7, 7.0 Hz, 1 H), 4.17 (dd, J = 11.7, 3.5 Hz, 1 H), 3.69 (d, J = 11.2 Hz, 3 H), 3.68 (d, J = 11.3 Hz, 3 H), 2.07 (s, 3 H), 2.05 (s, 3 H), 2.03 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 169.5, 169.5, 158.1 (d, J = 22.7 Hz), 97.4 (d, J = 201.7 Hz), 74.7, 66.1 (d, J = 9.8 Hz), 63.4 (d, J = 3.7 Hz), 61.0, 52.6 (d, J = 5.1 Hz), 52.6 (d, J = 5.7 Hz), 21.0, 20.9, 20.8.
31P NMR (162 MHz, CDCl3): δ = 20.5.
IR: 2956, 2361, 1745, 1622, 1369, 1224, 1188, 1026, 829, 781 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C14H21NaO10P+: 403.0765; found: 403.0770.
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2-(Diisopropylphosphonate)-3,4,6-tri-O-acetyl-d-glucal (2j)
Compound 2j was obtained by following the general procedure for phosphonylation using Pd(OAc)2 (2.2 mg, 10 mol%, 0.01 mmol), XPhos (14.3 mg, 30 mol%, 0.03 mmol), 1a (40 mg, 1 equiv, 0.1 mmol), DIPEA (52.2 μL, 3 equiv, 0.3 mmol), triisopropylphosphite (37.0 μL, 1.5 equiv, 0.15 mmol) and DMF/iPrOH (0.4 mL, 1:1), and the resulting mixture was stirred for 1 h at 70 °C. Compound 2j was obtained after purification on silica gel (cHex/EtOAc, 1:1 then 2:8 then 0:100).
Yield: 40 mg (0.091 mmol, 91%); yellowish oil; [α] d 20 +9.5 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 10.4 Hz, 1 H), 5.51 (dd, J = 6.4, 4.1 Hz, 1 H), 5.10–5.06 (m, 1 H), 4.67–4.55 (m, 2 H), 4.44 (m, 1 H), 4.39 (dd, J = 11.8, 7.2 Hz, 1 H), 4.16 (dd, J = 11.8, 3.7 Hz, 1 H), 2.06 (s, 3 H), 2.02 (s, 3 H), 2.01 (s, 3 H), 1.29–1.25 (m, 12 H).
13C NMR (101 MHz, CDCl3): δ = 170.6, 169.5, 169.5, 156.8 (d, J = 23.4 Hz), 100.1 (d, J = 202.9 Hz), 74.4, 70.8 (d, J = 5.8 Hz), 70.7 (d, J = 5.8 Hz), 66.3 (d, J = 9.7 Hz), 63.2 (d, J = 3.5 Hz), 61.2, 24.2 (d, J = 4.5 Hz), 24.2 (d, J = 4.9 Hz), 24.1 (d, J = 4.2 Hz), 23.9 (d, J = 4.6 Hz), 21.0, 20.9, 20.8.
31P NMR (162 MHz, CDCl3): δ = 15.3.
IR: 2980, 2358, 1743, 1622, 1369, 1217, 1182, 975, 897, 773 cm–1.
HRMS (TOF ES+): m/z [M + Na]+ calcd. for C18H29NaO10P+: 459.1391; found: 459.1395.
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Procedures for Deprotection
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Deacetylation of 2a
Compound 2a (55 mg, 0.135 mmol) was dissolved in EtOH (2 mL). K2CO3 (5 mg, cat.) was added and the resulting mixture was stirred at r.t. for 4 h. The mixture was concentrated under vacuum and 2c was obtained after purification on silica gel (CH2Cl2/MeOH, 9:1).
Yield: 35 mg (0.124 mmol, 92%); colorless oil.
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Debenzylation of 2a
Compound 2b (40 mg, 0.072 mmol) was dissolved in EtOH (1.5 mL). PdCl2 (5.6 mg, 40 mol%) was added and the reaction vessel was placed under H2 atmosphere (8 bar). The resulting mixture was stirred at r.t. overnight. The mixture was filtrated on Celite with EtOH and then concentrated under vacuum. Compound 2c was obtained after purification on silica gel (CH2Cl2/MeOH, 9:1).
Yield: 11 mg (0.039 mmol, 54%); colorless oil.
#
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1709-3305.
- Supporting Information
-
References
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- 7h Esteves HA, Darbem MP, Pimenta DC, Stefani HA. Eur. J. Org. Chem. 2019; 7384
- 7i Mestre J, Lishchynskyi A, Castillon S, Boutureira O. J. Org. Chem. 2018; 83: 8150
- 7j Mestre J, Castillon S, Boutureira O. J. Org. Chem. 2019; 84: 15087
- 7k Soares-Paulino AA, Stefani HA. Eur. J. Org. Chem. 2020; 3847
- 7l Darbem MP, Esteves HA, de Oliveira IM, Pimenta DC, Stefani HA. ChemCatChem 2020; 12: 576
- 7m Malinowski M, Tran TV, de Robichon M, Lubin-Germain N, Ferry A. Adv. Synth. Catal. 2020; 362: 1184
- 8 Al-Shuaeeb RA. A, Montoir D, Alami M, Messaoudi S. J. Org. Chem. 2017; 82: 6720
- 9 Malinowski M, Banoun C, de Robichon M, Lubin-Germain N, Ferry A. Eur. J. Org. Chem. 2021; 1521
- 10 Hirao T, Masunaga T, Ohshiro Y, Agawa T. Synthesis 1981; 56
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Selected articles:
Corresponding Author
Publication History
Received: 15 October 2021
Accepted after revision: 30 November 2021
Accepted Manuscript online:
30 November 2021
Article published online:
26 January 2022
© 2021. Thieme. All rights reserved
Georg Thieme Verlag KG
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-
References
- 1a Wang Z, Cole PA. Methods Enzymol. 2014; 548: 1
- 1b Cheng H.-C, Qi RZ, Paudel H, Zhu H.-J. Enzyme Res. 2011; 794089
- 1c Saier MH. Jr. J. Mol. Microbiol. Biotechnol. 2001; 3: 325
- 1d Deutscher J, Aké FM. D, Derkaoui M, Zébré AC, Cao TN, Bouraoui H, Kentache T, Mokhtari A, Milohanic E, Joyet P. Microbiol. Mol. Biol. Rev. 2014; 78: 231
- 2a Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L. Int. J. Mol. Med. 2017; 40: 271
- 2b Pawson T, Scott JD. Trends Biochem. Sci. 2005; 30: 286
- 3a Deutscher J, Francke C, Postma PW. Microbiol. Mol. Biol. Rev. 2006; 70: 939
- 3b Roy S, Vivoli Vega M, Harmer NJ. Catalysts 2019; 9: 29
- 3c Somavanshi R, Ghosh B, Sourjik V. PLOS Biol. 2016; 14: e2000074
- 4a Hoffmeister D, Yang J, Liu L, Thorson JS. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 13184
- 4b Yang J, Fu X, Jia Q, Shen J, Biggins JB, Jiang J, Zhao J, Schmidt JJ, Wang PG, Thorson JS. Org. Lett. 2003; 5: 2223
- 4c Ritte G, Heydenreich M, Mahlow S, Haebel S, Kötting O, Steup M. FEBS Lett. 2006; 580: 4872
- 5a Nicotra F. Top. Curr. Chem. 1997; 187: 55
- 5b Yang Y, Yu B. Chem. Rev. 2017; 117: 12281
- 5c Lee DY. W, He M. Curr. Top. Med. Chem. 2005; 5: 1333
- 6 Dharuman S, Vankar YD. Org. Lett. 2014; 16: 1172
- 7a Rodriguez MA, Boutureira O, Matheu MI, Diaz Y, Castillon S, Seeberger PH. J. Org. Chem. 2007; 72: 8998
- 7b Hussain N, Bhardwaj M, Ahmed A, Mukherjee D. Org. Lett. 2019; 21: 3034
- 7c Jana S, Rainier JD. Org. Lett. 2013; 15: 4426
- 7d Cobo I, Matheu MI, Castillon S, Boutureira O, Davis BG. Org. Lett. 2012; 14: 1728
- 7e Chemler SR, Iserloh U, Danishefsky SJ. Org. Lett. 2001; 3: 2949
- 7f Bordessa A, Ferry A, Lubin-Germain N. J. Org. Chem. 2016; 81: 12459
- 7g de Robichon M, Bordessa A, Lubin-Germain N, Ferry A. J. Org. Chem. 2019; 84: 3328
- 7h Esteves HA, Darbem MP, Pimenta DC, Stefani HA. Eur. J. Org. Chem. 2019; 7384
- 7i Mestre J, Lishchynskyi A, Castillon S, Boutureira O. J. Org. Chem. 2018; 83: 8150
- 7j Mestre J, Castillon S, Boutureira O. J. Org. Chem. 2019; 84: 15087
- 7k Soares-Paulino AA, Stefani HA. Eur. J. Org. Chem. 2020; 3847
- 7l Darbem MP, Esteves HA, de Oliveira IM, Pimenta DC, Stefani HA. ChemCatChem 2020; 12: 576
- 7m Malinowski M, Tran TV, de Robichon M, Lubin-Germain N, Ferry A. Adv. Synth. Catal. 2020; 362: 1184
- 8 Al-Shuaeeb RA. A, Montoir D, Alami M, Messaoudi S. J. Org. Chem. 2017; 82: 6720
- 9 Malinowski M, Banoun C, de Robichon M, Lubin-Germain N, Ferry A. Eur. J. Org. Chem. 2021; 1521
- 10 Hirao T, Masunaga T, Ohshiro Y, Agawa T. Synthesis 1981; 56
- 11 Demmer CS, Krogsgaard-Larsen N, Bunch L. Chem. Rev. 2011; 111: 7981
- 12 Di Bussolo V, Caselli M, Pineschi M, Crotti P. Org. Lett. 2003; 5: 2173
Selected articles:
