Reaction #164435

Reaction equation

N-Acetyl-β-neuraminic Acid Benzyl ester

Carbobenzyloxy-L-Valine

1-Chloro-N,N,-2-trimethyl-1-propenylamine

→

( 1-5 )

Yield 32.0%

5-Acetylamino-6-[3-(2-benzyloxycarbonylamino-3-methyl-butyryloxy)-1,2-dihydroxy-propyl]-2,4-dihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester

Yield 32.0%

Solvents

pyridine

dichloromethane

Conditions

Workup

1. 1
   workup.ADDITIONby dropwise addition via a syringe
2. 2
   Otherresulting in a clear colorless solution
3. 3
   workup.WAITThe solution immediately turns yellow and is kept at 0° C. and under an argon atmosphere for 3 hours
4. 4
   OtherThe cooling bath is then removed
5. 5
   workup.WAITthe solution kept at rt for overnight
6. 6
   Otherresulting in a cloudy suspension
7. 7
   OtherThe solvents are removed under high vacuum
8. 8
   Otherdoes not exceed 50° C.
9. 9
   Otherto give a light yellow oil
10. 10
    OtherIn order to remove traces of pyridine
11. 11
    Otherthe oil is triturated with toluene
12. 12
    Otheragain evaporated under high vacuum
13. 13
    workup.DISSOLUTIONThe remaining oil is dissolved in minimum amount of dichloromethane (DCM)
14. 14
    Otherpurified by flash chromatography (Mobile Phase: DCM/Methanol=96/4 to 88/12 over 24 minutes)

Procedure

To a solution of Carbobenzyloxy-L-Valine (1.35 g, 5.37 mmol) in anhydrous dichloromethane (12 mL) at 0° C. under argon is added 1-Chloro-N,N,-2-trimethyl-1-propenylamine (848 μL, 6.34 mmol) by dropwise addition via a syringe. The resulting solution is then stirred at 0° C. for 10 minutes resulting in a clear colorless solution. To this solution is then added the N-Acetyl-β-neuraminic Acid Benzyl ester (1-2), previously dissolved in anhydrous pyridine (8.0 mL) via dropwise addition. The solution immediately turns yellow and is kept at 0° C. and under an argon atmosphere for 3 hours. The cooling bath is then removed and the solution kept at rt for overnight resulting in a cloudy suspension. The solvents are removed under high vacuum being careful that the temperature bath does not exceed 50° C. to give a light yellow oil. In order to remove traces of pyridine, the oil is triturated with toluene and again evaporated under high vacuum. The remaining oil is dissolved in minimum amount of dichloromethane (DCM) and loaded directly unto a silica gel column (Silicycle-FLH-R10030B-ISO80, 80 g Cartridge) and purified by flash chromatography (Mobile Phase: DCM/Methanol=96/4 to 88/12 over 24 minutes). Combination of the purest fractions yields 996 mg (32% yield) of pure (1-5) as a white solid. LC/MS: (+) ESI: m/z=633.2 [M+1]; 655.2 [M+Na, major signal); retention time=3.69 min. 1H NMR (400 MHz, d4-MeOD) δ 7.12-7.37 (m, 11H), 5.08-5.17 (m, 2H), 4.95-5.03 (m, 2H), 4.28 (dd, J=11.6, 2.0 Hz, 1H, C-9), 4.18 (dd, J=11.6, 6.0 Hz, 1H, C-9′), 4.05-4.06 (m, 1H), 3.91-3.98 (m, 1H), 3.89 (dd, J=10.5, 1.2 Hz, 1H), 3.80-3.86 (m, 11H), 3.70 (t, 1H), 3.41-3.43 (m, 1H), 2.14 (dd, J=12.8, 4.8 Hz, 1H), 1.98-2.08 (m, 1H), 1.91 (s, 3H), 1.79-1.89 (m, 1H), 0.80-0.84 (m, 6H); 13C NMR (400 mHz, d4-MeOD) δ 173.7, 170.9, 158.9, 136.2, 137.1, 129.6, 129.5, 129.4, 129.1, 129.0, 128.8, 96.7, 72.0, 70.3, 69.3, 68.3, 68.0, 67.8, 61.1, 54.4, 40.7, 32.1, 22.7, 19.6, 18.4.

Source