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1 Current address: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden. Fax: +46(8)154908
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12 We observed that Mannich product 1 was unstable and racemized if stored at room temperature or subjected to silica gel column chromatography. In addition, 1 is prone to epimerization that decreases the diastereomeric ratio.
13 The reaction proceeded in other solvents as well at 23 °C: Dioxane: 65% yield, dr>10:1, 99% ee; THF: 51% yield, dr>10:1, 99% ee; Et2O: 40% yield, dr>10:1, 99% ee; and at 4 °C: THF: 36% yield, dr>10:1, >99% ee; dioxane: 62% yield, dr>10:1, 99% ee.
14 Anhydrous DMF (3 mL) was added to a vial containing the aldimine (0.5 mmol) and proline (30 mol%) and placed in a 4 °C cold room. The reaction was initiated by slow addition (0.2 mL/min) of a pree-cooled mixture of propionaldehyde (5.0 mmol) in anhyd DMF (2 mL) with syringe pump at 4 °C. After 15 h the reaction mixture was diluted with anhyd Et2O (2 mL) and the temperature decreased to at 0 °C followed by reduction with NaBH4 (400 mg) for 10 min. Next, the reaction mixture was poured into a vigorously stirred bi-phaseic solution of Et2O and 1 M aq HCl. The organic layer was separated and the aq phase was extracted thoroughly with EtOAc. The combined organic phases were dried (MgSO4), concentrated, and purified by flash column chromatography (silica gel, mixtures of hexanes/EtOAc) to afford 2. (2
S
,3
S
)-2-Methyl-3-(4-methoxyphenylamino)-3-(4-nitrophenyl)-propan-1-ol (2): 1H NMR (CDCl3): δ = 0.91 (d, 3 H, J = 7.0 Hz), 2.21 (m, 1 H), 3.64 (m, 2 H), 3.67 (s, 3 H, OMe), 4.65 (d, 1 H, J = 4.0 Hz), 6.42 (d, 2 H, J = 8.8 Hz), 6.68 (d, 2 H, J = 8.8 Hz), 7.51 (d, 2 H, J = 8.8 Hz), 8.17 (d, 2 H, J = 8.8 Hz). 13C NMR: δ = 11.9, 41.6, 56.0, 60.8, 66.0; 115.0, 115.1, 123.9, 128.3, 141.0, 147.3, 150.6, 152.6. HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm): major isomer: t
R = 36.10 min; minor isomer: t
R
= 21.49 min; [α]D = -65.2 (c 0.2, MeOH). HRMS: 317.1496; C17H20N2O4 [(M + H+): calcd 317.1496]; C17H20N2O4 (316.1423).
15
(1
S
,2
S
)-1-(4-Methoxyphenylamino)-1-(4-nitrophenyl)-2-hydroxymethylheptane: 1H NMR (CD3OD): δ = 0.83 (t, 3 H, J = 7.0 Hz), 1.22-1.55 (m, 8 H), 2.08 (m, 1 H), 3.54 (d, 1 H, J = 3.3 Hz), 3.68 (s, 3 H, OMe), 3.73 (d, J = 3.3 Hz), 4.71 (d, J = 3.3 Hz), 6.48 (d, 2 H, J = 8.8 Hz), 6.68 (d, 2 H, J = 8.8 Hz). 13C NMR: δ = 14.4, 22.9, 27.8, 29.7, 46.4, 56.1, 63.9, 96.6, 115.3, 124.1, 128.7, 147.5. HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 90:10, flow rate 1.0 mL/min, λ = 254 nm): major isomer: t
R = 17.79 min; minor isomer: t
R = 7.43 min; [α]D = -24.7 (c 0.2, MeOH). HRMS: 373.2120; C21H28N2O4 [(M + H+): calcd 373.2122); C21H28N2O4 (372.2048968).
16 Anhydrous DMF (3 mL) was added to a vial containing p-nitrobenzaldehyde (0.5 mmol), p-anisidine (0.5 mmol) and proline (30 mol%) and placed in a 4 °C cold room. The reaction was initiated by slow addition (0.2 mL/min) of a pree-cooled mixture of propionaldehyde (5.0 mmol) in anhyd DMF (2 mL) with syringe pump at 4 °C. After 16 h of total reaction time the temperature was decreased to 0 °C followed by dilution with anhyd Et2O (2 mL) and reduction with NaBH4 (400 mg) for 10 min. Next, the reaction mixture was poured into a vigorously stirred bi-phaseic solution of Et2O and 1 M aq HCl. The organic layer was separated and the aqueous phase was extracted thoroughly with EtOAc. The combined organic phases were dried (MgSO4), concentrated, and purified by flash column chromatography (silica gel, mixtures of hexanes/EtOAc) to afford 2.
17a NMR-data of the major diastereomer of PMP-deprotected 6 was identical to the previously reported syn-diastereomer, see: Jaeger V.
Buss V.
Schwab W.
Liebigs Ann. Chem.
1980,
122
17b
(2
S
,3
S
)-3-Amino-2-methyl-3-phenylpropan-1-ol (9): 1H NMR (CD3OD): δ = 1.10 (d, 3 H, J = 4.4 Hz), 2.35 (m, 1 H), 3.44 (d, 1 H, J = 5.14 Hz), 3.48 (d, 1 H, J = 6.6 Hz), 4.35 (d, 1 H, J = 6.6 Hz), 7.54 (m, 5 H). 13C NMR: δ = 12.0, 40.9, 59.1, 66.2, 126.9, 127.1, 128.2, 143.9.
17c
l-Proline derived 6 had the same retention time as (2S,3S)-6 that had been synthesized via known procedures, see: Vicario JL.
Badía D.
Carrillo L.
J. Org. Chem.
2001,
66:
9030
17d See also: Vicario JL.
Badía D.
Carrillo L.
Org. Lett.
2001,
3:
773; HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm): t
R = 14.02 min
18
(2
S
,3
S
)-2-Methyl-3-(4-methoxyphenylamino)-3-phenylpropan-1-ol (6): 1H NMR (CD3OD): δ = 0.95 (d, 3 H, J = 7.0 Hz), 2.05 (m, 1 H), 3.38 (dd, 1 H), 3.56 (dd, 1 H), 3.62 (s, 3 H, OMe), 4.43 (d, 1 H, J = 4.0 Hz), 6.38 (d, 2 H, J = 8.8 Hz), 6.50 (d, 2 H, J = 8.8 Hz), 7.12 (m, 1 H), 7.24 (m, 2 H); 7.31 (d, 2 H, J = 7.7 Hz). 13C NMR: δ = 12.8, 43.7, 56.3, 61.4, 66.0, 115.7, 116.0, 127.7, 128.6, 129.3, 143.9, 144.6, 151.9, 153.1, 157.7. HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm): major isomer: t
R = 14.02 min; minor isomer: t
R = 12.18; [α]D = -6.2. (c 1, MeOH). HRMS: 272.1647; C17H21NO2 [(M + H+): calcd 272.1645); C17H21NO2 (271.172206).