Solid-Phase Synthesis of β-Mono-Substituted Ketones and an Application to the Synthesis of a Library of Phlorizin Derivatives

Abstract

We describe a novel reaction sequence for the solid-phase synthesis of β-mono-substituted ketones. The methodology involves an aldol condensation reaction, followed by reduction of the resultant double bond and allows the introduction of a range of alkyl chains to solid-linked ketones at α position. Using the methodology we accomplished the synthesis of phlorizin library of 132 compounds using 43 aldehydes and four glycosyl bromides.

solid-phase synthesis - β-mono-substituted ketone - aldol condensation - rhodium catalized reductions - phlorizin

References

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ArgoGel^TM-Wang-Cl resin was purchased from Argonaut Technologies, San Carlos, CA.

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Yield (%) was calculated based on weight of isolated products and based on the initial loading of resin. Purity was determined by LC-MS analysis employing UV detection at 254 nm.

<A NAME="RY07702ST-9">9</A>

Column: Mightysil RP-18 GP (ODS) 3 µm, 4.6 mmI. D. × 50 mm; mobile phase: 20 mM AcONH₄: MeOH = 70:30 (0 min.)-10: 90 (4-8 min.); UV: 254 nm.

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Spectral data; 19: ¹H NMR (270 MHz, CDCl₃): δ =12.30 (1 H, s), 7.71 (1 H, d, J = 7.9 Hz), 7.44 (1 H, t, J = 7.9 Hz), 7.37-7.14 (5 H, m), 6.97 (1 H, d, J = 7.9 Hz), 6.85 (1 H, t,
J = 7.9 Hz), 3.30 (2 H, t, J = 8.3 Hz), 3.05 (2 H, t, J = 8.3 Hz); ¹³C NMR (67.8 MHz, CDCl₃): δ = 205.3, 162.4, 140.7, 136.3, 129.8, 126.3, 119.2, 118.9, 118.5, 77.5, 77.0, 76.5, 39.9, 29.9; MS (ESI): 227 [M + H⁺].

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<A NAME="RY07702ST-14">14</A> The loading amount of ketone was determined by acidic cleavage after removal of THP group, followed by mass recovery and HPLC analysis

<A NAME="RY07702ST-15">15</A> Yield (%) was calculated based on weight of isolated products and based on the loading amount of 2′, 6′-dihydroxyacetophenone. Purity was determined by LC-MS analysis employing UV detection at 254 nm.

<A NAME="RY07702ST-16">16</A>

Spectral data; ¹H NMR (270 MHz, CDCl₃): δ = 9.50-9.28 (2 H, brs), 7.37-7.17 (8 H, m), 3.47 (2 H, t, J = 7.9 Hz), 3.04 (2 H, t, J = 7.9 Hz); MS (ESI): 243 [M + H⁺].

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<A NAME="RY07702ST-18">18</A>

Spectral data; ¹H NMR (300 MHz, CDCl₃): δ = 9.71-9.58 (1 H, br s), 9.56 (1 H, s), 7.22 (1 H, t, J = 8.1 Hz), 7.16 (2 H, d, J = 8.4 Hz), 6.84 (2 H, d, J = 8.4 Hz), 6.39 (2 H, d, J = 8.1 Hz), 3.79 (3 H, s), 3.43 (2 H, t, J = 8.1 Hz), 2.98 (2 H, t, J = 8.1 Hz); MS (ESI): 273 [M + H⁺].

<A NAME="RY07702ST-19">19</A> Zenkoh T. Tanaka H. Setoi H. Takahashi T. Synlett  2002,  867 

<A NAME="RY07702ST-20">20</A>

General procedure for the solid-phase synthesis of phlorizin derivatives exemplified with the synthesis of 27: The resin 21 (2 × 30 mg, 0.17 mmol/g) was loaded into IRORI^TM MicroKans. To a solution of benzaldehyde (35 µL) in EtOH (1.75 mL) and 50% KOH aq (0.35 mL) were added the MicroKans at ambient temperature. After being shaken for 17 hours at the same temperature, the reaction mixture was drained to isolate the Kans. The Kans were sequentially washed with DMF (4 × 3 mL), 5% AcOH-THF (2 × 3 mL), THF-H₂O (2:1, 2 × 3 mL), THF (4 × 3 mL), MeOH (4 × 3 mL), and CH₂Cl₂ (4 × 3 mL) and dried in vacuo to give immobilized enone 22a in two Kans. Two MicroKans were exposed to a solution of (Ph₃P)₃RhCl (72 mg) and Et₃SiH (125 µL) in benzene (2.0 mL). After being shaken at ambient temperature for 16 hours, the mixture was drained. Remaining two Kans were washed sequentially with benz-ene (3 mL), DMF (4 × 3 mL), 5% AcOH-THF (4 × 3 mL), THF (4 × 3 mL), MeOH (4 × 3 mL), and CH₂Cl₂ (4 × 3 mL) and dried to give ketone 23a. To a solution of p-TsOH
(42 mg) in CH₂Cl₂-MeOH (5: , 2.1 mL) were added the MicroKans at ambient temperature and the mixture was shaken for 20 hours. The reaction mixture was drained to isolate the Kans. The Kans were sequentially washed with MeOH (4 × 3 mL), dioxane (4 × 3 mL), DMF (4 × 3 mL), and CH₂Cl₂ (4 × 3 mL) and then dried in vacuo to afford immobilized phenol 24a in two Kans. The MicroKans were exposed to a solution of glucosyl bromide 25 (168 mg) in 1,2-dichloroethane (2.8 mL). To the mixture were suc-cessively added 5% NaOH aq (1.4 mL) and benzyl tri-n-butylammonium chloride (14.6 mg). After being shaken at ambient temperature for 15.5 hours, the mixture was drained. Remaining two Kans were washed sequentially with CH₂Cl₂ (3 mL), DMF (4 × 3 mL), THF-H₂O (2:1,
2 × 3 mL), 5% AcOH-THF (2 × 3 mL), THF (4 × 3 mL), MeOH (4 × 3 mL), and CH₂Cl₂ (4 × 3 mL) and dried to give protected glycoside 26. To a solution of Cs₂CO₃ (74 mg) in THF-MeOH (1:1, 2.0 mL) were added the MicroKans at ambient temperature. After being shaken for 18 hours at the same temperature, the reaction mixture was drained to isolate the Kans. The Kans were sequentially washed
with THF-MeOH (1:1, 4 × 3 mL), DMF (4 × 3 mL), THF-water (2:1, 2 × 3 mL), 5% AcOH-THF (2 × 3 mL), THF
(4 × 3 mL), MeOH (4 × 3 mL), and CH₂Cl₂ (4 × 3 mL). The resin in the two MicroKans was cleaved with 10% TFA-CH₂Cl₂ (5.0 mL) for 30 minutes. The resulting solution was diluted with CH₂Cl₂ (5 mL) and toluene (2 mL). The MicroKans were removed from the solution by means of tweezers. The acidic solution was concentrated to afford 27 (3.6 mg, 8.90 µmol, 87% yield with 79% purity). Spectrum data of 27: ¹H NMR (300 MHz, DMSO-d₆): δ = 10.97 (1 H, s), 7.30-7.13 (6 H, m), 6.67 (1 H, d, J = 8.8 Hz), 6.55 (1 H, d, J = 8.1 Hz), 5.26 (1 H, d, J = 4.8 Hz), 5.13 (1 H, d, J = 5.1 Hz), 5.06 (1 H, d, J = 5.9 Hz), 4.91 (1 H, d, J = 7.3 Hz), 4.59 (1 H, t, J = 5.5 Hz), 3.74-3.65 (2 H, m), 3.52-3.10 (6 H, m), 2.90 (2 H, t, J = 7.5 Hz); MS (ESI): 422 [M + NH₄ ⁺].

<A NAME="RY07702ST-21A">21a</A> Nicolaou KC. Xiao XY. Parandoosh Z. Senyei A. Nova MP. Angew. Chem., Int. Ed. Engl.  1995,  34:  2289 

<A NAME="RY07702ST-21B">21b</A>

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