A. Mandoli et al. / Tetrahedron: Asymmetry 15 (2004) 3233–3244
3241
Compound 6b: TLC Rf = 0.61 (Pet. ether:Et2O = 3:1).
1H NMR d: 1.5–1.8 (m, 4H), 2.43 (s, 3H), 3.41 (t,
J = 6Hz, 2H), 4.05 (t, J = 6Hz, 2H), 4.44 (s, 2H), 7.2–
7.4 (m, 7H), 7.80 (d, J = 8Hz, 2H). 13C NMR (CDCl3)
d: 21.4, 25.5, 25.7, 69.0, 70.3, 72.6, 127.3, 127.6, 128.1,
129.6, 132.9, 138.2, 144.5.
4.2.4. Malonyl dichloride 9b. A two-necked 50mL flask,
equipped with a dropping funnel, was charged with the
acid 8b (4.8mmol), dry CH2Cl2 (8mL), and DMF
(50lL). After cooling in an ice bath, oxalyl chloride
(14mmol) was added dropwise over 1.5h and the mixture
was allowed to warm at room temperature and stirred
overnight. The volatiles were removed under reduced
pressure (20mmHg), affording the acid chloride 9b as dark
yellow oils, pure enough for the use in the following step.
4.2.2. Diethyl malonate 7b. A 100mL two-necked flask,
equipped with a dropping funnel and a reflux condenser,
was charged with 50% NaH in mineral oil (ꢀ24mmol)
and, after washing with dry hexane (2 · 5mL), the hy-
dride was suspended in dry THF (18mL). While cooling
in an ice bath, diethyl methylmalonate (19.6mmol), was
added dropwise to the rapidly stirred mixture. When the
gas evolution had ceased (30min), the resulting suspen-
sion was allowed to warm to room temperature and a
solution of the tosylate 6b (21.5mmol) in THF (10mL)
was added dropwise. The mixture was heated and kept
under reflux until disappearance (GC) of the starting
malonic ester (24h). After cooling in an ice bath, the
resulting suspension was cautiously treated with satu-
rated NH4Cl solution (40mL) and most of the organic
solvent removed with a rotary evaporator. The resulting
mixture was extracted with Et2O (3 · 30mL) and the
combined organic phases were washed with water until
neutral and dried over Na2SO4. The solvent was
removed under reduced pressure and the residue was
purified by distillation, obtaining 7b as a colorless
liquid in 70% yield.
Compound 9b: 1H NMR d: 1.3–1.7 (m, 7H), 2.0–2.1 (m,
2H), 3.48 (t, J = 7Hz, 2H), 4.49 (s, 2H), 7.2–7.5 (m, 5H).
13C NMR d: 20.3, 20.7, 29.5, 35.3, 69.3, 73.0, 127.5,
127.6, 128.3, 138.2, 171.4.
4.2.5. Bis(hydroxyamides) (S,S)-10a and (S,S)-10b.Gen-
eral procedure. A 50mL two-necked flask, equipped
with a dropping funnel, was charged with (S)-phenyl-
glycinol (8mmol, 2equiv), dry CH2Cl2 (8.5mL), and
Et3N (20mmol, 5equiv). While cooling at 0ꢁC, a
solution of the crude acid chloride 9a or 9b (4mmol)
in CH2Cl2 (3.5mL) was added dropwise over 0.5h to
the rapidly stirred solution. After 1h the resulting sus-
pension was diluted with CH2Cl2 (20mL) and washed
sequentially with HCl 1N (25mL), satd NaHCO3 solu-
tion (20mL), and brine (20mL), back-extracting each
time the aqueous layer with CH2Cl2 (10mL). The com-
bined organic phases were dried over Na2SO4 and the
removal of the solvent under reduced pressure (35ꢁC,
20mmHg) afforded the amides 10a and 10b as off-white
solids, which could be directly used in the following step.
For characterization purposes, samples of the products
were purified by flash chromatography (10a, 80% yield)
or crystallization from AcOEt (10b, 50% yield).
Compound 7b: Bp123 ꢁC (5 · 10À3 mmHg). 1H NMR d:
1.21 (t, J = 8Hz, 3H), 1.2–1.4 (m, 2H), 1.40 (s, 3H), 1.5–
1.9 (m, 4H), 3.84 (t, J = 6Hz, 2H), 4.54 (q, J = 8Hz,
4H), 4.87 (s, 2H), 7.2–7.4 (m, 5H). 13C NMR d: 13.9,
19.7, 20.9, 29.9, 35.2, 53.6, 61.0, 69.9, 72.8, 127.4,
127.5, 128.3, 138.5, 172.3.
25
(S,S)-10a: Mp127–128 ꢁC. ½a ¼ þ40:0 (c 1.0, MeOH).
D
IS-ms (m/z) 545 (M + H)+. IR (KBr): 3321, 2930, 2862,
1638, 1543, 1456, 1361, 1284, 1258, 1107, 1062, 1026,
1
4.2.3. Malonic acid 8b. A 25mL two-necked flask,
equipped with a reflux condenser, was charged with
the ester 7b (11mmol) and 4mL of 18M KOH solution
(CAUTION). The biphasic mixture was heated under
reflux, until disappearance of the upper organic layer
(2–3h), cooled to room temperature, diluted with water
(20mL), and extracted with Et2O (2 · 5mL). After plac-
ing in an ice bath, to the rapidly stirred aqueous solution
37% HCl was cautiously added, adjusting the pH below
2. The resulting white suspension was extracted with
AcOEt (3 · 20mL), washing the combined organic
phases with water (3 · 10mL). Removal of the solvent
under reduced pressure afforded the malonic acid 8b as
a white solid in 80% yield. NMR analysis confirmed that
the product was pure enough to be used in the following
stepwithout further purification.
823, 755, 700, 642, 529. H NMR d: 1.2–1.4 (m, 2H),
1.46 (s, 3H), 1.5–1.6 (m, 2H), 1.8–1.9 (m, 2H), 3.38 (t,
J = 6Hz, 2H), 3.7–3.9 (m, 4H), 4.43 (s, 2H), 5.0–5.1
(m, 2H), 5.22 (d, J = 10Hz, 1H), 5.72 (d, J = 16Hz,
1H), 6.70 (dd, J1 = 10Hz, J2 = 16Hz, 1H), 7.1–7.5 (m,
17H). 13C NMR d: 19.4, 21.4, 29.7, 38.1, 53.8, 55.70,
55.76, 65.9, 69.8, 72.4, 113.7, 126.5, 127.7, 127.8,
128.7, 136.5, 138.7, 173.3, 173.8.
25
(S,S)-10b: Mp149–150 ꢁC. ½a ¼ þ52:7 (c 1.0, MeOH).
D
IS-ms (m/z) 519 (M + H)+, 536 (M + NH4)+,
541 (M + Na)+. IR (KBr): 3311, 2922, 2856, 1733,
1639, 1544, 1494, 1450, 1361, 1283, 1255, 1100, 1072,
1
1028, 800, 756, 733, 694, 644, 527. H NMR d: 1.2–1.3
(m, 2H), 1.46 (s, 3H), 1.5–1.6 (m, 2H), 1.9–2.0 (m,
2H), 3.17 (br s, 2H), 3.38 (t, J = 6Hz, 2H), 3.7–3.9 (m,
4H), 4.43 (s, 2H), 5.0–5.1 (m, 2H), 7.2–7.3 (m, 17H).
13C NMR d: 19.3, 21.3, 29.7, 38.1, 53.7, 55.6, 55.7,
65.8, 69.9, 72.8, 126.5, 127.5, 127.6, 128.3, 128.7,
138.7, 173.2, 173.7.
Compound 8b: Mp110–111 ꢁC. IS-ms (m/z) À279
(MÀH+)À. IR (KBr): 2954, 2872, 1748, 1706, 1462,
1413, 1371, 1297, 1215, 1198, 1162, 1122, 1093, 1070,
1
978, 946, 909, 870, 768, 748, 732, 699, 663. H NMR
d: 1.2–1.7 (m, 7H), 1.8–2.0 (m, 2H), 3.45 (t, J = 8Hz,
2H), 4.50 (s, 2H), 7.2–7.4 (m, 5H), 9.70 (br s, 2H). 13C
NMR d: 19.9, 21.1, 29.6, 35.4, 53.7, 69.7, 72.8, 127.6,
127.8, 128.3, 138.0, 177.6.
4.2.6. Bis(oxazolines) (S,S)-11a and (S,S)-11b.General
procedure. A 50mL two-necked flask, equipped with a
dropping funnel, was charged with the bis(amide) 10a or
10b (3.9mmol) and dry CH2Cl2 (15mL), followed by