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PAPER
EtOAc) to give (2R,3S)-diol (20.0 g, 89%); yellow oil; [a]D23 +4.9
(c 1.1, CHCl3).
(2R,3R)-9
[a]D22 –3.1 (c 1.0, CHCl3); 99% ee.
IR (film): 3428, 2970, 2929, 1732, 1610, 1539, 1447, 1392, 1366,
1219, 1102, 1005, 837 cm–1.
Ethyl (2S,3R)-2-trans-Aziridine-3-(4¢-methoxyethoxymethox-
yphenyl)-2-propanoate [(2S,3R)-10]
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H), 2.65 (d,
J = 6.8 Hz, 1 H), 3.10 (d, J = 5.9 Hz, 1 H), 3.39 (s, 3 H), 3.55 (m, 2
H), 3.81 (m, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.30 (m, 1 H), 4.94 (m,
1 H), 5.27 (s, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 2
H).
To a stirred solution of (2S,3S)-9 (87.5 mg, 0.230 mmol) in MeCN
(1.5 mL) was added Ph3P (120 mg, 0.459 mmol). The mixture was
heated at 40 °C for 22 h and then concentrated in vacuo. H2O (5 mL)
and EtOAc (20 mL) were added to the residue. The organic layer
was dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (4:1 hexane–
EtOAc) to give (2S,3R)-10 (72 mg, 93%); yellow oil; [a]D23 –142.6
(c 1.0, CHCl3).
13C NMR (100 MHz, CDCl3): d = 14.1, 58.9, 62.0, 67.5, 71.5, 74.2,
75.0, 93.3, 115.9, 127.6, 133.4, 156.8, 172.5.
HRMS-FAB: m/z [M + H]+ calcd for C15H22O7: 314.1366; found:
314.1366.
IR (film): 3272, 2966, 1719, 1608, 1508, 1437, 1402, 1337, 1214,
1167, 1102, 1003, 814 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H), 2.54 (m,
1 H), 3.21 (d, J = 4.6 Hz, 1 H), 3.37 (s, 3 H), 3.55 (m, 2 H), 3.81 (m,
2 H), 4.21–4.29 (m, 2 H), 5.25 (s, 2 H), 6.99 (d, J = 8.8 Hz, 2 H),
7.19 (d, J = 8.5 Hz, 2 H).
Intermediate (2S,3R)-Diol
[a]D22 –5.0 (c 1.1, CHCl3).
Step 2; Intermediate a-Nosyl Product: To a solution of (2R,3S)-
diol (1.30 g, 4.20 mmol) in DMF (14 mL) were added Et3N (1.20
mL, 8.30 mmol) and 4-nitrobenzensulfonyl chloride (1.40 g, 6.30
mmol). The solution was stirred at –10 °C for 56 h, and then H2O
(20 mL) and Et2O (100 mL) were added. The organic layer was
washed with brine (50 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (4:1 hexane–EtOAc) to give the a-nosyl product
(2.60 g, 98%); colorless oil; [a]D23 +45.0 (c 1.5, CHCl3).
13C NMR (100 MHz, CDCl3): d = 14.4, 39.5, 40.1, 59.1, 61.9, 67.7,
71.7, 93.5, 116.3, 127.3, 131.2, 156.9, 171.7.
HRMS-FAB: m/z [M + H]+ calcd for C15H22NO5: 296.1498; found:
296.1499.
(2R,3S)-10
[a]D25 +156.4 (c 1.2, CHCl3).
IR (film): 3420, 3106, 2923, 1742, 1737, 1611, 1532, 1375, 1344,
1310, 1225, 1187, 1094, 1009, 850, 839, 747 cm–1.
Ethyl (2S,3S)-2-tert-Butoxycarbonylamino-3-(4¢-methoxy-
ethoxymethoxyphenyl)-3- methoxypropanoate [(2S,3S)-6c]
To a solution of (2S,3R)-10 (526 mg, 1.68 mmol) in MeOH–CH2Cl2
(1:2, 1.8 mL) was added BF3·OEt2 (0.212 mL, 1.68 mmol) at –78
°C. After stirring at –78 °C for 26 h, the mixture was added to sat.
aq NH4Cl (2 mL). To the mixture was added EtOAc (10 mL) and
the organic layer was washed with brine (5 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo to give the crude amino alcohol. To
a solution of the crude amino alcohol in THF (2.5 mL) were added
Et3N (0.620 ml, 4.47 mmol) and (Boc)2O (650 mg, 2.98 mmol). Af-
ter stirring for 20 h at r.t., H2O (5 mL) and EtOAc (10 mL) were
added. The organic layer was dried (MgSO4), filtered, and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (2:1 hexane–EtOAc) to give (2S,3S)-6c (498 mg,
67%); colorless oil; [a]D27 –3.5 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.19 (t, J = 7.1 Hz, 3 H), 2.78 (s,
1 H), 3.35 (s, 3 H), 3.54 (m, 2 H), 3.81 (m, 2 H), 4.16 (q, J = 7.1 Hz,
2 H), 4.97 (d, J = 4.2 Hz, 1 H), 5.15 (s, 1 H), 5.23 (s, 2 H), 6.89 (d,
J = 8.5 Hz, 2 H), 7.14 (d, J = 8.5 Hz, 2 H), 7.85 (d, J = 8.8 Hz, 2 H),
8.23 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 59.0, 62.5, 67.8, 71.6, 73.1,
82.5, 93.4, 116.1, 124.1, 127.4, 129.1, 130.7, 141.4, 150.5, 157.4,
166.4.
HRMS-FAB: m/z [M + H]+ calcd for C15H22O7: 314.1366; found:
314.1369.
Enantiomer of a-Nosyl Product
[a]D22 –43.2 (c 0.6, CHCl3).
Azide (2S,3S)-9: To a stirred solution of the respective a-nosyl
product (919 mg, 1.84 mmol) in DMF (6 mL) was added NaN3 (599
mg, 9.21 mmol) at r.t. The mixture was heated at 55 °C for 45 h and
then cooled down to r.t. H2O (10 mL) and EtOAc (30 mL) were add-
ed and the organic layer was washed with brine (20 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The residue was pu-
rified by column chromatography on silica gel (2:1 hexane–EtOAc)
IR (film): 3363, 2979, 2933, 1747, 1716, 1610, 1510, 1367, 1165,
1101, 1020, 1005, 867 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.26 (m, 3 H), 1.34–1.40 (s, 9 H),
3.31 (s, 3 H), 3.38 (s, 3 H), 3.56 (m, 2 H), 3.82 (m, 2 H), 4.23 (m, 2
H), 4.50 (m, 1 H), 4.56 (m, 1 H), 5.14 (d, J = 8.8 Hz, 1 H), 5.27 (s,
2 H), 7.04 (d, J = 6.6 Hz, 2 H), 7.22 (t, J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.2, 28.2, 57.2, 58.4, 61.4, 67.6,
71.6, 79.6, 82.5, 93.5, 116.1, 128.1, 130.5, 155.4, 157.2, 170.3.
22
to give (2S,3S)-9 (382 mg, 54%); yellow oil; [a]D +3.1 (c 1.0,
CHCl3).
HRMS-FAB: m/z [M + Na]+ Calcd for C21H33NO8 + Na: 450.2104;
found: 450.2108.
IR (film): 3307, 2931, 2358, 2108, 1737, 1612, 1514, 1377, 1261,
1174, 1102, 1026, 838 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 3 H), 3.39 (s,
3 H), 3.56 (m, 2 H), 3.73 (m, 2 H), 4.09 (d, J = 7.1 Hz, 1 H), 4.25
(m, 2 H), 4.97 (d, J = 7.1 Hz, 1 H), 5.24 (s, 2 H), 6.99 (d, J = 8.8 Hz,
2 H), 7.26 (d, J = 8.5 Hz, 2 H).
(2R,3R)-6d
[a]D27 +2.4 (c 1.1, CHCl3).
H-Gln-bMeOTyr-N-Me-Ala-OMe [(2S,3R)-4a]; Typical Proce-
dure
13C NMR (100 MHz, CDCl3): d = 14.2, 59.1, 62.2, 66.9, 67.7, 71.6,
73.7, 93.4, 116.3, 127.9, 132.3, 157.5, 168.9.
To a solution of (2S,3R)-6a (200 mg, 0.470 mmol) in t-BuOH–H2O
(1:1, 3 mL) was added LiOH (39 mg, 0.940 mmol). The mixture
was stirred for 2 h at r.t. and the solvent was removed in vacuo. The
residue was extracted with EtOAc (10 mL) and the organic layer
was washed with H2O (5 mL), dried (MgSO4), and evaporated in
vacuo. To a solution of the residue in DMF (2 mL) were added N-
HRMS-FAB: m/z [M + Na]+ calcd for C15H21N3O6 + Na: 362.1328;
found: 362.1332.
The enantiomeric excess was determined to be 99% ee by the Mosh-
er method.17
Synthesis 2007, No. 23, 3666–3672 © Thieme Stuttgart · New York