combined organic layers were washed with 5% NaHCO3 aque-
ous solution (50 ml) and 25% NaCl aqueous solution, and then
dried over anhydrous MgSO4, and concentrated under reduced
pressure at 40–45 ЊC to give crude (S)-5b (58.1 g, purity: 86.4%
by HPLC, net 126 mmol, quantitative from 4b) as a yellowish
oil. This material was used in the subsequent transformation
without further purification.
mixture was concentrated to about 50 ml under reduced
pressure at 35–40 ЊC. Water (50 ml) and dichloromethane
(150 ml) were added to the concentrate and extracted, and the
aqueous layer was then extracted again with dichloromethane
(50 ml). The combined organic layers were concentrated under
reduced pressure to give crude (2S,3S)-8b (17.5 g) as a colorless
solid. The peak area of the diastereomer ((2R,3S)-form) was
about 16% in an HPLC analysis. A portion (1.0 g) of the crude
material was recrystallized from n-hexane–ethyl acetate (1/1)
(15 ml) to give pure crystals (0.6 g, (2R,3S)/(2S,3S) = 98.5/1.5).
The remaining material was used in the subsequent trans-
formation without further purification.
1H NMR (300 MHz, CDCl3) δ = 1.44 (s, 9H), 2.99 (dd, 1H,
J = 7.1, 14.1 Hz), 3.17 (dd, 1H, J = 6.1, 14.1 Hz), 3.38 (m, 2H),
4.68 (bq, 1H, J = approx. 7 Hz), 5.07 (s, 2H), 5.38 (bd, 1H,
J = 7.9 Hz), 7.12–7.35 (m, 10H); 13C NMR (75 MHz, CDCl3)
δ = 28.0, 37.1, 48.2, 60.7, 67.0, 82.4, 127.1, 128.1, 128.2, 128.5,
128.7, 129.2, 135.8, 137.9, 165.8, 182.0, 201.7; MS (ϩFAB) m/z
398 (MHϩ); HRMS (ϩFAB) calcd for C23H28NO5 (MHϩ),
398.1967, found 398.1949.
1H NMR (300 MHz, CDCl3) (2S,3S) form δ = 2.87 (dd, 1H,
J = 9.0, 14.1 Hz), 3.00 (dd, 1H, J = 4.6, 14.1 Hz), 3.55 (dd, 1H,
J = 7.3, 11.3 Hz), 3.60 (bs, 1H), 3.62 (dd, 1H, J = 4.3, 11.3 Hz),
3.86 (bq, 1H, J = approx. 5 Hz), 3.96–4.06 (m, 1H), 5.01 (s, 2H),
5.31 (bd, 1H, J = approx. 8.5 Hz), 7.18–7.33 (m, 10H); 13C
NMR (75 MHz, CDCl3) (2S,3S) form δ = 35.3, 47.1, 54.6, 66.5,
73.2, 126.4, 127.8, 127.9, 128.3, 128.3, 129.3, 136.3, 137.5,
156.0; mp = 153–154 ЊC; [α]2D5 Ϫ24.5 (c 0.56, CH3OH); MS
(ϩFAB) m/z 333.8 (MHϩ); HRMS (ϩFAB) calcd for
C18H21ClNO3 (MHϩ), 334.1210, found 334.1184.
tert-Butyl(4S )-4-N-benzyloxycarbonylamino-2-chloro-3-oxo-
5-phenylpentanoate (6b). Sulfuryl chloride (7.23 ml, 90 mmol)
was added dropwise to a solution of (S)-5b (40.5 g, purity:
86.4%, net 88 mmol) in dichloromethane (88 ml) in an ice bath
with stirring over 30 min at a rate sufficient to maintain the
temperature at 10 ЊC. When the addition was complete, the ice
bath was removed and the reaction was continued with stirring
for 30 min at 20 ЊC. The resulting mixture was concentrated
under reduced pressure at 25–30 ЊC to give crude (S)-6b (48.6 g)
as pale yellowish crystals. A portion (2.0 g) of the crude
material was recrystallized from toluene (10 ml) to give pure
crystals. The remaining material was used in the subsequent
transformation without further purification.
(1S,1ЈS )-1-(1Ј-N-Benzyloxycarbonylamino-2Ј-phenyl)ethyl-
oxirane (9b). To a solution of crude 8b (16.5 g, prepared as
above) in methanol (600 ml) was added portionwise anhydrous
K2CO3 (14.1 g, 102 mmol). After the mixture was stirred at
ambient temperature for 3 h, the suspended salts were removed
by filtration and were washed with methanol (20 ml). The
combined filtrate and washing liquor were concentrated to
about 100 ml under reduced pressure at 35 ЊC. Dichloro-
methane (150 ml) and 0.5 M HCl (100 ml) were added to the
concentrate and extracted, and the aqueous layer was then
extracted again with dichloromethane (150 ml). The combined
organic layers were concentrated under reduced pressure below
40 ЊC to give 9b (14.0 g, 47.1 mmol, containing about 16% of
the diastereoisomer, 97.6% yield from (S)-7b (2 steps), 82%
yield as the (1S,1ЈS) form), as a colorless solid. A portion (1.0
g) of the crude material was recrystallized from n-hexane–ethyl
acetate (1/1) (6 ml) to give pure crystals (0.58 g, (1S,1ЈS)/
(1R,1ЈS) = 98.5/1.5). Another portion of remaining material
was used in the subsequent transformation without further
purification.
1H NMR (300 MHz, CDCl3) δ = 1.44 (s, 9H), 2.99 (dd, 1H,
J = 7.5, 14.1 Hz), 3.20 (dd, 1H, J = 6.1, 14.1 Hz), 4.85 (s, 1H),
4.97 (bq, 1H, J = 8.4 Hz), 5.06 (s, 2H), 5.25 (bd, 1H, J = 8.4 Hz),
7.14–7.35 (m, 10H); 13C NMR (75 MHz, CDCl3) δ = 27.5, 37.7,
59.5, 60.0, 67.2, 85.0, 127.3, 128.1, 128.3, 128.5, 128.9, 129.2,
135.3, 136.0, 155.6, 163.1, 197.4; mp = 79–80 ЊC; [α]2D5 Ϫ47.2
(c 1.05, CH3OH); MS (ϩFAB) m/z 431.8 (MHϩ); HRMS
(ϩFAB) calcd for C23H27ClNO5 (MHϩ), 432.1578, found
432.1568.
(3S )-1-Chloro-2-oxo-3-N-benzyloxycarbonylamino-4-phenyl-
butane (7b). Crude crystals of (S)-6b (46.6 g, prepared as
above) were added to 90% formic acid (80 ml) at ambient tem-
perature and the suspended mixture was heated in an oil bath
with stirring for 20 min at 80 ЊC. The resulting mixture was
cooled to ambient temperature, concentrated under reduced
pressure at 30–35 ЊC, and then concentrated again in the same
manner after the addition of isopropanol (100 ml) to com-
pletely remove formic acid. To the residual solid was added
isopropanol (200 ml) which had been warmed to 60 ЊC. The
mixture was recrystallized at 5 ЊC, filtered, washed with cold
isopropanol (50 ml), and dried at 40 ЊC in vacuo to give (S)-7b
(20.1 g, 60 mmol, 68.2% from (S)-5b (2 steps)) as slightly
yellowish crystals.
1H NMR (300 MHz, CDCl3) (1S,1ЈS) form δ = 2.71–2.80
(m, 2H), 2.85 (dd, 1H, J = 8.1, 14.1 Hz), 2.91 (dd, 1H, J = 2.7,
6.4 Hz), 2.97 (dd, 1H, J = 5.1, 14.1 Hz), 3.68–3.82 (m, 1H), 4.77
(bd, 1H, J = 5.9 Hz), 5.03 (s, 2H), 7.17–7.33 (m, 10H); 13C
NMR (75 MHz, CDCl3) (1S,1ЈS) form δ = 37.5, 46.7, 53.0,
53.2, 66.8, 126.8, 128.0, 128.1, 128.5, 128.6, 129.3, 136.2,
136.4, 155.7; mp = 77–80 ЊC; MS (ϩFAB) m/z 297.9 (MHϩ);
HRMS (ϩFAB) calcd for C18H20NO3 (MHϩ), 298.1443, found
298.1456.
1H NMR (300 MHz, CDCl3) δ = 3.00 (dd, 1H, J = 7.0, 13.9
Hz), 3.09 (dd, 1H, J = 6.9, 13.9 Hz), 3.97 (d, 1H, J = 16.2 Hz),
4.14 (d, 1H, J = 16.2 Hz), 4.75 (bq, 1H, J = approx. 7 Hz), 5.06
(s, 2H), 5.38 (bd, 1H, J = 7.6 Hz), 7.11–7.38 (m, 10H); 13C
NMR (75 MHz, CDCl3) δ = 37.6, 47.3, 58.7, 67.2, 127.4, 128.1,
128.3, 128.5, 128.9, 129.0, 135.2, 135.9, 155.7, 200.8; mp = 109–
111 ЊC; [α]2D5 Ϫ51.1 (c 1.06, CH3OH); MS (ϩFAB) m/z 331.8
(MHϩ); HRMS (ϩFAB) calcd for C18H19ClNO3 (MHϩ),
332.1053, found 332.1041.
(2R,3S )-3-N-Benzyloxycarbonylamino-2-hydroxy-1-N-iso-
butylamino-4-phenylbutane (10b). A solution of crude 9b (4.47
g, 15.0 mmol, (1S,1ЈS)/(1R,1ЈS) = 84/16) in ethanol (29 ml) was
added in one portion to isobutylamine (22.4 ml, 225 mmol).
The resulting mixture was heated in an oil bath with stirring for
60 min at 70 ЊC, and then concentrated under reduced pressure
to remove the solvent and excess isobutylamine. Volatile matter
was completely removed in vacuo to give crude 10b (6.08 g,
(2R,3S)/(2S,3S) theoretically 84/16, quantitative) as a colorless
solid. This material was used in the subsequent transformation
without further purification.
(2S,3S )-1-Chloro-2-hydroxy-3-N-benzyloxycarbonylamino-4-
phenylbutane (8b). Sodium borohydride (2.03 g, 53.8 mmol) was
added portionwise over 10 min with stirring to a solution
of (S)-7b (17 g, 51.2 mmol) in a mixture of dichloromethane
(180 ml) and methanol (180 ml) that had been cooled to Ϫ3 ЊC.
After the mixture was stirred for 30 min at 0 ЊC, acetic acid
(12.9 ml, 226 mmol) was added to quench the reaction, and the
1H NMR (300 MHz, CDCl3) (2S,3S) form δ = 0.90 (d, 6H,
J = 6.6, Hz), 1.60–1.80 (m, 1H), 2.38 (d, 2H, J = 6.8 Hz), 2.65
(dd, 1H, J = 6.8, 12.4 Hz), 2.70 (dd, 1H, J = 4.0, 12.4 Hz), 2.7
(bs, 1H), 2.86 (dd, 1H, J = 8.1, 14.1 Hz), 2.99 (dd, 1H, J = 4.8,
14.1 Hz), 3.49 (bq, 1H, J = approx. 4.5 Hz), 3.80–3.95 (m, 1H),
5.02 (s, 2H), 5.11 (bd, 1H, J = 9.0 H), 7.19–7.32 (m, 10H); 13C
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 6 1 – 2 0 7 0
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