Synthesis of the Azetidinyl-Thiazoline Fragment
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
357
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evaporated to dryness and partitioned between water and
ether. Usual workup gave an oil that was purified by flash
chromatography (AcOEt), to afford 12 (1.17 g, quant.).
[ꢀ]D20: -67 (c 1.3, CHCl3); 1H NMR: 1.19 (d, J = 6.9 Hz, 3H,
Me), 2.67 (bs, 1H, OH), 3.03-3.14 (m, 1H, CHMe), 3.43 (dd,
J = 8.3 and 0.6, 1H CHHOH), 3.46-3.58 (m, 3H, CHHOH
and CHHCN), 3.63 d, part of AB syst., J = 13.3 Hz, 1H,
NCHH), 3.79 (s, 3H, OMe), 3.81 (d, part of AB syst., J =
13.3 Hz, 1H, CHHN), 6.88 (d, J = 8.7 Hz, 2H, Ar), 7.24 (d, J
= 8.7 Hz, 2H, Ar); 13C NMR: 11.8, 38.2, 52.5, 55.3, 59.3,
63.5, 114.5, 116.9, 129.1, 130.2, 159.3; CIMS (NH3): 207.8,
121.2; Anal. Calc. For C13H18N2O2 (234.9): C: 66.64; H:
7.74; N: 11.96. Found: C: 66.52; H: 7.92; N: 11.79.
(EP/AcOEt: 1/1); Mp: 98°C; [ꢀ]D20: -21 (c 0.5, CHCl3); H
NMR: 1.03 (d, J = 6.3 Hz, 3H, Me), 2.21 (bs, 1H, OH), 3.16-
3.23 (m, 1H, CHMe), 3.44-3.57 (m, 4H, CH2OH and
CH2CN) 5.05 (s, 1H, CHAr2), 7.14-7.40 (m, 6H, Ar), 7.45-
7.54 (m, 4H, Ar); 13C NMR: 16.5, 37.2, 55.2, 64.5, 72.3,
118.4, 127.9, 128.6, 143.3; Anal. Calc. For C16H19NO
(241.3): C: 79.63; H: 7.94; N: 5.80. Found: C: 79.71; H:
8.02; N: 5.71.
(R)-N-Allylloxycarbonyl-alaninol 15
Following the procedure for the preparation of 16,
starting from 13.3 mmol of 10, title compound 15 was
obtained as an oil after purification by flash chromatography
(1/1 PE/AcOEt). Yield 1.7 g, 80%). [ꢀ]D20: +12 (c 0.8,
CHCl3); 1H NMR (d6-acetone): 1.14 (d, J = 6.8 Hz, 3H, Me),
3.42-3.56 (m, 2H, CH2O), 3.64-3.77 (m, 1H, CHMe), 3.95 (t,
J = 4.6 Hz, 1H, OH), 4.50 (d, J = 5.2 Hz, 2H, CH2O), 5.13-
5.31 (m, 2H, CHCH2), 5.85-5.99 (m, 1H, CHCH2), 6.11 (bs,
1H, NH); 13C NMR: 17.7, 49.8, 65.4, 66.3, 117.1, 134.7,
156.7; CIMS (NH3): 177, 160, 128, 119, 102; Anal. Calc.
For C7H13NO3 (159.2): C: 52.82; H: 8.23; N: 8.80. Found: C:
52.64; H: 8.24; N: 8.78.
(R)-N-Benzhydryl-alaninol 13
To a solution of (R)-alaninol 10 (520 mg, 6.9 mmol) in
DCM (15 mL) was added benzaldehyde (0.7 mL, 6.9 mmol)
and 4Å molecular sieves (2g). After 4h at rt, the mixture was
filtrated on Celite and evaporated under reduced pressure.
The resulting oil was dissolved in ether (50 mL) and the
solution was cooled to 0°C. Phenyllithium (2M solution in
Bu2O, 8.5 mL, 17 mmol) was then added dropwise. After 12
h at rt, the mixture was hydrolyzed by careful addition of a
saturated aqueous solution of ammonium chloride. Usual
(R)-N- Benzyloxycarbonyl-alaninol 16
To a solution of (R)-alaninol 10 (2 g, 26.6 mmol) and
potassium carbonate (7.4 g, 53.5 mmol), in 1/1 THF/water
(50 mL) was added at 0°C benzyloxycarbonyl chloride (4.2
mL, 29.3 mmol). The reaction mixture was stirred for 1h at rt
and water (50 mL) was then added. Usual workup gave 16 as
crystals that were washed with small amounts of cold PE.
Compound 16 was obtained as white crystals (5.6 g, quant.).
workup gave
a residue that was purified by flash
chromatography (EP/AcOEt: 1/1) to give 13 as a light
orange oil (0.89 g, 53%). Rf: 0.35 (EP/AcOEt: 1/1); [ꢀ]D20: -
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39 (c 1.2, CHCl3); H NMR: 1.00 (d, J = 6.3 Hz, 3H, Me),
2.05 (bs, 2H, OH, NH), 2.87-2.74 (m, 1H, CHMe), 3.20 (d, J
= 10.8 Hz, 1H CHHOH), 3.48 (d, J = 10.8 Hz, 1H CHHOH),
3.46-3.58 (m, 3H, CHHOH and CHHCN), 3.63 (d, part of
AB syst., J = 13.3 Hz, 1H, NCHH), 4.94 (s, 1H, CHAr2),
7.11-7.34 (m, 10H, Ar); 13C NMR: 17.2, 51.8, 66.1, 69.5,
126.2, 126.9, 127.2, 127.4, 128.3, 128.6, 128.7, 143.3, 144.3;
CIMS (NH3): 370, 334, 295, 281, 264, 242, 196; Anal. Calc.
For C16H19NO (241.3): C: 79.63; H: 7.94; N: 5.80. Found: C:
79.71; H: 8.02; N: 5.71.
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Mp: 81°C; [ꢀ]D20: +5 (c 1.5, CHCl3); H NMR (d6-acetone):
1.00 (d, J = 6.7 Hz, 3H, Me), 3.29-3.43 (m, 2H, CH2O),
3.52-3.65 (m, 1H, CHMe), 4.91 (s, 2H, ArCH2O), 7.13-7.27
(m, 5H, Ar); 13C NMR: 17.8, 48.1, 66.3, 66.5, 128.6, 128.7,
129.2, 138.9, 156.3; CIMS (NH3): 126.2, 108.1, 91.2; Anal.
Calc. For C11H15NO3 (209.22): C: 63.14; H: 7.23; N: 6.69.
Found: C: 63.21; H: 7.32; N: 6.61.
(R)-N-Benzhydryl-N-cyanomethyl-alaninol 14
(R)-N-tert-Butoxycarbonyl-alaninol 17
To a solution of 13 (720 mg, 3 mmol) in toluene (15 mL)
was added paraformaldehyde (290 mg, 9 mmol) and p-
toluenesulfonic acid (57 mg). The solution was refluxed
azeotropically for 3h, concentrated under reduced pressure
and the residue was purified by flash chromatography
(EP/AcOEt: 75/25) to give the corresponding oxazolidine
13a (0.52 g, 69%). Rf: 0.78 (EP/AcOEt: 1/1); [ꢀ]D20: +16 (c
To a solution of (R)-alaninol 10 (1 g, 13.3 mmol) and
triethylamine (1.9 mL, 13.5 mmol), in THF (40 mL) was
added at 0°C di-tert-butyl-dicarbonate (2.9 g, 13.3 mmol).
The reaction mixture was stirred for 2h at rt. Concentration
under reduced pressure and partition of the residue in water
and ether was followed by usual workup. The crude product
was recrystallized from hot hexane (10 mL) and AcOEt (2
mL). Compound 17 was obtained as white crystals (2.2 g,
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0.6, CHCl3); H NMR: 1.00 (d, J = 6.6 Hz, 3H, Me), 3.15-
3.22 (m, 2H, CHMe, CHHO), 3.96-4.01 (m, 1H, CHHO),
4.21 (d, J = 6.6 Hz, 1H, NCHHO), 4.28 (d, J = 6.9 Hz, 1H,
NCHHO), 4.76 (s, 1H, CHAr2), 7.07-7.24 (m, 6H, Ar); 7.43-
7.52 (m, 4H, Ar); Anal. Calc. For C17H19NO (253.3): C:
80.60; H: 7.56; N: 5.53. Found: C: 80.45; H: 7.74; N: 5.49.
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93%). Mp: 55°C; [ꢀ]D20: -6 (c 0.8, CHCl3); H NMR: 1.12
and 1.13 (rotamers) (two bd, J = 6.3 Hz, 3H, Me), 1.42 and
1.43 (rotamers) (two bs, Boc), 3.46-3.50 (bm, 1H, CHHO),
3.53-3.62 (bm, 1H, CHHO), 3.67-3.79 (bm, 1H, CHMe),
4.83 (bs, 1H, NH); 13C NMR: 17.3, 28.4 and 28.6 (rotamers),
48.6, 67.0, 79.6, 156.3; Anal. Calc. For C8H17NO3 (175.2):
C: 54.84; H: 9.78; N: 7.99. Found: C: 54.94; H: 9.86; N:
7.96.
This oxazolidine (0.4 g, 1.57 mmol) was dissolved into
dry ethanol (15 mL), anhydrous citric acid ( 0.302 g, 1.57
mmol) and potassium cyanide (0.378 g, 5.81 mmol) were
successively added. The solution was refluxed for 2.5 h and
neutralized by addition of aqueous NaHCO3. Concentration
under reduced pressure was followed by partition between
aqueous NaHCO3 and ether. Usual workup gave a residue
that was purified by flash chromatography (CyH / AcOEt:
8/2), to give 14 as white crystals (0.26 g, 60%). Rf: 0.59
General Procedure for the Preparation of Compounds
18-20
To a solution of the required N-protected amino alcohol
15-17 (10.7 mmol) in toluene (50 mL) and parafor-