H.-J. Ha et al.
Bull. Chem. Soc. Jpn., 74, No. 9 (2001) 1671
α
1H, J = 5.8, 4.1 Hz), 3.34 (s, 3H), 3.63 (s, 3H), 3.66–3.78 (m,
3H), 7.12–7.26 (m, 5H); 13C NMR δ 14.0, 22.5, 26.1, 29.1, 29.5,
30.5, 31.7, 50.8, 51.5, 58.6, 58.8, 82.0, 126.7, 128.0, 128.1, 140.6,
172.4.
(3R,4S)-3-methoxy-1-[(S)- -methylbenzyl]-4-phenylazeti-
din-2-one 1H NMR δ 1.24 (d, 3H), 2.90 (s, 3H), 4.37 (d, 1H),
4.45 (d, 1H), 5.01 (q, 1H), 7.18–7.39 (m, 10H); 13C NMR δ 19.0,
51.7, 58.0, 60.9, 84.8, 127.4, 127.9, 128.1, 128.5, 128.7, 128.8,
135.2, 139.5, 166.8. [α]2D2 +68.9° (c 0.48, CH2Cl2). Anal. Calcd
for C18H19NO2: C, 76.8; H, 6.81; N, 4.98%. Found: C, 76.6; H,
6.73; N, 4.74%.
α
β α
Synthesis of Methyl -Methoxy- -( -methylbenzyl)amino
Carboxylate. The reactions were carried out in the same way as
for the compounds 14 with the imines (9–12) derived from (R)- or
(S)-α-methylbenzylamine instead of benzylamines.
α
Methyl (2R,3S)-4-Cyclohexyl-2-hydroxy-3-[(S)- -methyl-
α
Methyl (2R,3S)-2-methoxy-3-[(S)- -methylbenzylamino]-3-
benzylamino]butyrate (23): 1H NMR δ 0.61–1.58 (m, 13H),
1.29 (3H, J = 6.4 Hz), 2.01 (brs, 2H), 2.98 (t, 1H, J = 6.8 Hz),
3.59 (q, 1H, J = 6.6 Hz), 3.82 (s, 3H), 4.00 (s, 1H), 7.17–7.43 (m,
5H); 13C NMR δ 24.1, 26.1, 26.3, 26.4, 33.0, 33.4, 34.0, 41.2,
52.2, 54.0, 55.9, 71.4, 126.4, 127.2, 128.4, 145.3, 175.4. [α]2D2
−56.6° (c 0.41, CH2Cl2). Anal. Calcd for C19H29NO3: C, 71.4; H,
9.15; N, 4.38%. Found: C, 71.7; H, 9.29; N, 4.18%.
phenylpropionate (18): 1H NMR δ 1.17 (d, 3H), 2.20 (brs, 1H),
3.22 (s, 3H), 3.51 (q, 1H), 3.54 (s, 3H), 3.78 (d, 1H), 4.11 (d, 1H),
7.09–7.24 (m, 10H); 13C NMR δ 21.7, 51.6, 54.1, 58.8, 61.9, 85.3,
126.6, 126.7, 127.5, 127.9, 128.2, 139.4, 145.9, 171.6. [α]2D2
+0.91° (c 0.93, CH2Cl2). Anal. Calcd for C19H23NO3: C, 72.8; H,
7.40; N, 4.47%. Found: C, 72.6; H, 7.69; N, 4.34%.
α
α
Methyl (2R,3S)-4-Cyclohexyl-2-methoxy-3-[(S)- -methyl-
(3R,4S)-4-Cyclohexylmethyl-3-methoxy-1-[(S)- -methyl-
benzylamino]butyrate (19). 1H NMR δ 0.61–1.58 (m, 13H),
1.24 (d, 3H, J = 6.4 Hz), 3.35 (s, 3H), 3.38–3.81 (m, 3H), 3.74 (s,
3H), 7.11–7.45 (m, 5H); 13C NMR δ 24.5, 26.0, 26.2, 26.4, 32.7,
33.6, 33.7, 39.9, 51.4, 53.8, 55.3, 58.6, 81.4, 126.7, 128.0, 128.3,
145.8, 172.5. [α]2D2 −36.7° (c 1.2, CH2Cl2). Anal. Calcd for
C20H31NO3: C, 72.0; H, 9.37; N, 4.20%. Found: C, 72.1; H, 9.51;
N, 4.42%.
benzyl]azetidin-2-one: 1H NMR δ 0.64–1.58 (m, 13H), 1.57 (d,
3H, J = 7.4 Hz), 3.47 (s, 3H), 3.49–3.54 (m, 1H), 4.28 (d, 1H, J =
4.4 Hz), 4.76 (q, 1H, J = 7.0 Hz), 7.12–7.33 (m, 5H); 13C NMR δ
19.9, 26.1, 26.2, 26.3, 33.1, 33.4, 34.4, 34.8, 36.3, 52.0, 56.4,
59.1, 83.3, 126.9, 127.6, 128.6, 140.2, 167.5. [α]2D2 +32.7° (c 1.2,
CH2Cl2).
α
Methyl (2S,3R)-2-Hydroxy-5-methyl-3-[(R)- -methylben-
zylamino]hexanoate (24): 1H NMR δ 0.64 (d, 3H, J = 6.8 Hz),
0.78 (d, 6H, J = 6.8 Hz), 1.25 (d, 3H, J = 6.8 Hz), 1.06–1.72 (m,
3H), 2.90 (dt, 1H, J = 7.2, 2.0 Hz), 3.63 (q, 1H, J = 6.8 Hz), 3.79
(s, 3H), 3.98 (d, 1H, J = 1.8 Hz), 7.12–7.60 (m, 5H). Anal. Calcd
for C16H25NO3: C, 68.7; H, 9.02; N, 5.01%. Found: C, 68.9; H,
9.25; N, 5.24%.
α
Methyl (2S,3R)-2-Methoxy-5-methyl-3-[(R)- -methylben-
zylamino]hexanoate (20): 1H NMR δ 0.56 (d, 3H, J = 6.6 Hz),
0.74 (d, 3H, J = 6.6 Hz), 1.12–1.19 (m, 5H), 1.31–1.65 (m, 2H),
2.63 (dt, 1H, J = 6.4, 1.8 Hz), 3.15 (s, 3H), 3.34 (s, 3H), 3.41–
3.62 (m, 2H), 6.97–7.07 (m, 5H); 13C NMR δ 21.7, 22.5, 24.1,
24.2, 41.2, 50.7, 54.3, 54.8, 58.2, 80.9, 126.5, 127.8, 145.6, 172.2.
[α]2D2 +40.3° (c 1.6, CH2Cl2). Anal. Calcd for C17H27NO3: C,
69.5; H, 9.28; N, 4.77%. Found: C, 69.4; H, 9.11; N, 4.49%
α
(3S,4R)-4-Isobutyl-3-methoxy-1-[(R)- -methylbenzyl]azeti-
din-2-one: 1H NMR δ 0.72 (d, 6H, J = 6.4 Hz), 0.78 (d, 3H, J
= 6.4 Hz), 1.19–1.62 (m, 7H), 3.52 (s, 3H), 4.31 (dt, 1H, J = 8.2,
2.1 Hz), 4.81 (q, 1H, J = 8.0 Hz), 7.25–7.33 (m, 5H); 13C NMR δ
19.7, 22.2, 22.9, 25.3, 37.6, 52.0, 56.8, 59.0, 83.3, 127.1, 127.7,
128.7, 140.1, 167.7. [α]2D2 −24.4° (c 0.56, CH2Cl2).
α
(2S,3R)-2-Methoxy-3-[(R)- -methylbenzylami-
Methyl
no]decanoate (21): 1H NMR δ 0.80 (t, 3H, J = 6.8 Hz), 0.94–
1.52 (m, 12H), 1.18 (d, 3H, J = 6.6 Hz), 1.53 (s, 1H), 2.74 (dt,
1H, J = 6.2, 3.0 Hz), 3.32 (s, 3H), 3.71 (s, 3H), 3.59–3.76 (m,
2H), 7.08–7.23 (m, 5H); 13C NMR δ 14.1, 22.6, 24.6, 26.2, 29.2,
29.4, 31.8, 32.1, 51.6, 55.5, 56.9, 58.9, 81.5, 126.8, 128.2, 146.0,
172.7. [α]2D2 +14.3° (c 0.74, CH2Cl2). Anal. Calcd for
C20H33NO3: C, 71.6; H, 9.91; N, 4.18%. Found: C, 71.6; H, 9.77;
N, 4.09%.
α
(2S,3R)-2-Hydroxy-3-[(R)- -methylbenzylami-
Methyl
no]decanoate (25): 1H NMR δ 0.82 (t, 3H, J = 7.4 Hz), 1.18–
1.69 (m, 12H), 3.48 (q, 1H, J = 6.0 Hz), 3.71 (s, 3H), 3.94 (d, 1H,
J = 1.9 Hz), 7.06–7.28 (m, 5H); 13C NMR δ 14.2, 22.6, 26.1,
29.1, 29.3, 31.7, 33.2, 52.1, 55.8, 56.8, 71.1, 126.4, 127.1, 128.4,
145.3, 173.5. [α]2D2 +24.9° (c 1.28, CH2Cl2). Anal. Calcd for
C19H31NO3: C, 70.9; H, 9.72; N, 4.36%. Found: C, 71.2; H, 9.88;
N, 4.52%.
α
β α
Synthesis of Methyl -Hydroxy- -( -methylbenzyl)amino
Carboxylate. BBr3 (10 mg, 0.40 mmol) was added into the so-
lution of methyl (2R,3S)-2-methoxy-3-[(S)-α-methylbenzylami-
no]-3-phenylpropionate (18) (376 mg, 1.20 mmol) in CH2Cl2 (30
mL) at −78 °C. The resultant reaction mixture was stirred for 2 h
at −78 °C before adding H2O (30 mL). The solution was neutral-
ized with 2M NaOH solution. The reaction product was extracted
with EtOAc (50 mL) three times. The extracts were washed by
100 mL each of water and brine, dried by anhydrous MgSO4, fil-
tered, and concentrated under reduced pressure. The crude prod-
uct was purified by flash column chromatography to give 269 mg
of methyl (2R,3S)-2-hydroxy-3-[(S)-α-methylbenzylamino]-3-
phenylpropionate (22) as the major product with 51 mg of lactam-
ized product (3R,4S)-3-hydroxy-1-[(S)-α-methylbenzyl]-4-pheny-
lazetidin-2-one as the minor one.
Methyl (2S,3R)-3-Benzoylamino-2-methoxydecanoate (26):
In CH3OH (15 mL) were dissolved Pd–C (60 mg) and compound
21 (291 mg, 0.87 mmol). Into this solution was introduced H2 gas
with a balloon; the mixture was stirred at rt until all starting mate-
rial was consumed on TLC for 15 h. The mixture was filtered and
concentrated under reduced pressure. This crude reaction product
was dissolved in a mixture of THF (5 mL) and water (5 mL). Ben-
zoyl chloride (122 mg, 0.87 mmol) was added dropwise to this so-
lution at 0 °C maintaining pH 9–10 with NaOH solution. After
addition was completed the resultant reaction mixture was stirred
vigorously for 30 min. The reaction product was extracted with
EtOAc (50 mL) three times. The extracts were washed by 100 mL
each of water and brine, dried by anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography to give 238 mg of the titled
compound in 82% yield. 1H NMR δ 0.81 (t, 3H, J = 7.0 Hz),
1.18–1.69 (m, 12H), 3.41 (s, 3H), 3.67 (s, 3H), 3.85 (s, 1H), 4.48
(q, 1H, J = 7.4 Hz), 6.31 (d, 1H, J = 8.8 Hz), 7.21–7.71 (m, 5H);
13C NMR δ 14.1, 22.6, 26.1, 29.1, 29.3, 31.7, 32.1, 51.8, 53.0,
α
Methyl (2R,3S)-2-Hydroxy-3-[(S)- -methylbenzylamino]-3-
phenylpropionate (22): 1H NMR δ 1.18 (d, 3H, J = 6.4 Hz),
3.54 (q, 1H, J = 6.4 Hz), 3.71 (s, 3H), 4.06 (d, 1H, J = 3.4 Hz),
4.19 (d, 1H, J = 3.4 Hz), 7.10–7.30 (m, 10H); 13C NMR δ 22.5,
52.4, 54.5, 61.4, 74.4, 126.5, 127.3, 127.4, 127.7, 128.5, 128.6,
140.2, 145.7. Anal. Calcd for C18H21NO3: C, 72.2; H, 7.07; N,
4.68%. Found: C, 72.4; H, 6.98; N, 4.74%.