Hydrochloric Acid → (3S,5R,6S)-tert-butyl 3-ethyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate

HRID 579484Notes

Reaction equation

HRID 579484 reaction equation
[O:1]=[C:2]1[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:3]1[CH2:27][CH2:28][CH2:29][CH2:30][B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1.CN([CH2:43][CH2:44]N(C)C)C.C(I)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl>COCCOC.CCCCCCC>[CH2:43]([C@:3]1([CH2:27][CH2:28][CH2:29][CH2:30][B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)[C:2](=[O:1])[O:7][C@@H:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:44]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 6340Iodoethane2×HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 3251421Potassium bis(trimethylsilyl)amide2×HCID 66833293tert-Butyl (3R,5R,6S)-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate

Product 1

HCID 66832819(3S,5R,6S)-tert-butyl 3-ethyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylateYield 65%

Reagents, catalysts & solvents 2

HCID 80711,2-DimethoxyethaneSolventHCID 8900HeptaneSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate (1.00 g, 1.87 mmol) and TMEDA (2 mL, 13 mmol, 7 equiv) in 1,2-dimethoxyethane (9.4 mL, 0.2 M) was cooled to −78° C. and treated with ethyl iodide (3 mL, 37 mmol, 20 equiv) and potassium bis(trimethylsilyl)amide (9.4 mL, 0.9 M in THF, 9.4 mmol, 5 equiv) drop wise. After stirring for an additional 30 min at −78° C., the cooling bath was removed and the mixture was stirred over night. The reaction was incomplete by TLC and therefore was recooled to −78° C. and treated with additional potassium bis(trimethylsilyl)amide (9.4 mL, 0.9 M in THF, 9.4 mmol, 5 equiv) and ethyl iodide (3 mL, 37 mmol, 20 equiv). After the additions were complete, the bath was removed and the solution was stirred overnight. Once complete by TLC, the reaction mixture was quenched with 0.5N HCl (5-10 equiv), diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3S,5R,6S)-tert-butyl 3-ethyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as colorless oil (0.68 g, 65%). Rf 0.40 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.31-7.15 (m, 10H), 7.08 (d, J=2.4 Hz, 1H), 6.02 (d, J=2.4 Hz, 1H), 2.35-2.22 (m, 2H), 2.22-2.07 (m, 2H), 1.47 (s, 9H), 1.26-1.21 (m, 4H), 1.15 (s, 12H), 1.00 (t, J=7.5 Hz, 3H), 0.85 (t, J=6.8 Hz, 2H); ESI-LCMS m/z calcd for C33H46BNO6: 563.3. found 564.3 (M+1)+.

Workup

  1. customthe cooling bath was removed
  2. stirringthe mixture was stirred over night
  3. customwas recooled to −78° C.
  4. customthe bath was removed
  5. stirringthe solution was stirred overnight
  6. washwashed successively with water and saturated aqueous NaCl
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification by MPLC (1-60% ethyl acetate in heptane over 6 CV)

Sources & evidence

ORD record
ord-0fe875c1c8274772be3681e781780b52
Source dataset
uspto-grants-2015_05
Patent number
US09040703B2

Reaction notes

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