M. Morita et al. / Tetrahedron: Asymmetry 16 (2005) 3176–3182
3179
dropwise over 1 h. After the addition of the solution, the
reaction mixture was additionally refluxed for 1 h.
29.8, 29.7, 29.5, 27.2 (–CH2–), 19.6, 14.1 (–CH3); IR
(KBr) 3300 (m), 2918, 2851 (s), 1636 (s), 1547 (m),
1468 (m), 721 (w), 696 (m) cmꢀ1; MS (EI) m/e 497
(M+, 16), 190 (16), 163 (46), 120 (39), 105 (100), 69
(27), 55 (48). Anal. Calcd for C34H59NO: C, 82.03; H,
11.95; N, 2.81. Found: C, 82.03; H, 12.22; N, 2.76.
4.5. (R)-3-Methylpentacos-16-enoic acid 10
To a suspension of CuI (17 mg, 0.1 mmol) in THF was
slowly added a solution of Grignard reagent 9 (26 mL,
11.2 mmol) in THF at 0 ꢁC under an argon atmosphere.
To this solution, (R)-(+)-b-methyl-b-propiolactone 4
(570 mg, 6.62 mmol) in THF (8 mL) was added drop-
wise. The mixture was stirred for 14 h at 0 ꢁC. After
complete consumption of 4, the reaction mixture was
quenched with 3M HCl aq (4 mL). The aqueous phase
was extracted with ether (5 · 3 mL), the combined
organic extracts washed with water (5 mL), brine (5 mL),
dried over anhydride Na2SO4, and concentrated to give
the crude carboxylic acid, which was purified by column
chromatography (silica gel, hexane/EtOAc = 85/15) to
4.7. (R)-3-Methylhexadecanedioic acid 12
To a solution of carboxylic acid 10 (251 mg, 0.64 mmol)
and K2CO3 (263 mg, 1.91 mmol) in acetone/H2O (1/1,
10 mL) was added a solution of KMnO4 (13 mg,
0.08 mmol) and NaIO4 (1.09 g, 5.08 mmol) in H2O
(10 mL) at room temperature. The mixture was stirred
at room temperature for 3 days. After complete con-
sumption of carboxylic acid 10, the reaction mixture
was filtered. The filtrate was acidified with 10% H2SO4
aq (5 mL), extracted with ether (5 · 3 mL), the organic
extracts washed with water (5 mL), dried over anhydride
Na2SO4, and concentrated to give the crude acid, which
was purified by column chromatography (silica gel, hex-
ane/EtOAc = 85/15) to give acid 12 (185 mg, 97%) as a
give carboxylic acid 10 (2.55 g, 98%) as a colorless
25
liquid: Rf = 0.46 (hexane/EtOAc = 70/30); ½aꢁD ¼ þ3:2
1
(c 1.1, CHCl3); H NMR (CDCl3, 300 MHz): d = 0.91
(d, J = 6.0 Hz, 3H, –CH3), 0.58–1.06 (m, 3H, –CH3),
1.06–1.60 (m, 34H, 17 · –CH2–), 1.80–2.45 (m, 7H,
–CH–, –CH2–C@C–CH2–, –CH2–CO–) 5.35 (t, J =
4.8 Hz, 2H, –CH@CH–); 13C NMR (CDCl3, 75 MHz):
d = 179.9 (–C@O), 130.4, 130.0 (C@C), 41.6, 36.7,
32.7, 32.0, 30.2, 29.81, 29.76, 29.71, 29.70, 29.60,
29.56, 29.4, 29.2, 27.2, 27.0, 22.7 (–CH2–), 19.7, 14.1
(–CH3); IR (neat) 3265–2759 (m/br), 3004, 2852 (s),
1708 (s), 1465 (m), 1296 (m), 721 (m) cmꢀ1; MS (EI)
m/e 395 (M++1, 0.2), 376 (5), 334 (5), 83 (34), 69 (50),
55 (100); HRMS (FAB) Calcd for C26H51O2 (MH+):
395.3889, found: 395.3873.
colorless powder: registry number 101592-14-7;
26
Rf = 0.42 (hexane/EtOAc = 40/60); ½aꢁD ¼ þ1:5 (c 1.0,
CHCl3) {lit.4d [a]D = +3.5 (c 5, CHCl3)}; 1H NMR
(CDCl3, 300 MHz): d = 0.96 (d, J = 6.6 Hz, 3H, –CH3),
1.1–1.4 (m, 20H, 10 · –CH2–), 1.52–1.70 (m, 2H,
HO2CCH2CH2–), 1.80–2.03 (m, 1H, –CH–), 2.15 (dd,
J = 14.7, 7.8 Hz, 1H, –CH(CH3)CHHCO2H), 2.23–
2.50 (m, 3H, –CH(CH3)CHHCO2H, –CH2CHHCO2H);
13C NMR (CDCl3, 75 MHz): d = 180.4, 178.0 (–C@O),
130.3, 129.9 (C@C), 41.7, 36.5, 34.1, 30.2, 29.6, 29.56,
29.50, 29.4, 29.3, 29.1, 29.01, 29.0, 26.8, 24.7 (–CH2–),
19.7 (–CH3); IR (KBr) 3323–3000 (m/br), 2918, 2851
4.6. (R)-N-(1-Phenylethyl)-3-methylpentacos-16-enamide
11
(s), 1706 (s), 1470 (w), 1200 (w) cmꢀ1
.
A solution of carboxylic acid 10 (145 mg, 0.5 mmol) in
oxalyl chloride (0.1 mL, 1.2 mmol) was refluxed for
3 h. Excess oxalyl chloride was removed under reduced
pressure. The crude carbonylchloride was dissolved in
ether (5 mL) and cooled to 0 ꢁC. To this solution a solu-
tion of (S)-1-phenylethylamine in ether (4.7 mL, 0.4 M)
was added at 0 ꢁC, then warmed to rt and stirred for
15 h. After complete consumption of carboxylic acid
10, the reaction mixture was quenched with 1 M HCl
aq (3 mL). The aqueous phase was extracted with ether
(5 · 3 mL), the combined organic extracts washed with
satd NaHCO3 aq (5 mL), water (5 mL), brine (5 mL),
dried over anhydride Na2SO4, and concentrated to
give the crude amide, which was purified by column
chromatography (silica gel, hexane/EtOAc = 90/10)
to give amide 11 (197 mg, 98%) as a colorless solid:
4.8. (R)-Dibenzyl 3-methylhexadecanedioate 13
Dicarboxylic acid 12 (246 mg, 0.82 mmol) and benzylal-
cohol (353 mg, 3.26 mmol) in toluene (10 mL) were
refluxed for 6 h in the presence of p-TsOHÆH2O (46 mg,
0.24 mmol) using a Dean–Stark trap. After complete
consumption of dicarboxylic acid 12, the reaction mix-
ture was cooled to room temperature and washed with
satd NaHCO3 aq (4 mL), H2O (4 mL) and brine
(4 mL). The organic solution was dried over anhydride
Na2SO4, and concentrated to give the crude diester,
which was purified by column chromatography (silica
gel, hexane/EtOAc = 95/5) to give diester 13 (353 mg,
90%) as a colorless liquid: Rf = 0.42 (hexane/EtOAc =
21
1
90/10); ½aꢁD ¼ þ1:1 (c 1.00, CHCl3); H NMR (CDCl3,
300 MHz): d = 0.92 (d, J = 6.6 Hz, 3H, –CH3),
1.05–1.40 (m, 20H, 10 · –CH2–), 1.55–1.70 (m, 2H,
–CH2CH2CO), 1.85–2.05 (m, 1H, –CH–), 2.15 (dd,
J = 8.0, 14.7 Hz, 1H, –CHCHHCO), 2.30–2.39 (m,
3H, CHCHHCO, –CH2CO), 5.11 (s, 4H, 2 · CH2Ar),
7.27–7.40 (m, 10H, 2 · Ar); 13C NMR (CDCl3,
75 MHz): d = 173.7, 173.2 (C@O), 136.1, 128.5, 128.2,
128.1 (Ar), 65.9, 65.9 (2 · PhCH2–), 41.7 (CH), 36.5,
34.2, 30.2, 29.6, 29.4, 29.3, 29.1, 28.9, 26.7, 24.8 (CH2),
19.6 (CH3); IR (neat), 2927, 2853 (s), 1736 (s), 1456
(m), 1163 (s) 696 (s) cmꢀ1; MS (EI) m/e 481 (M+, 0.3),
1
Rf = 0.29 (hexane/EtOAc = 80/20); H NMR (CDCl3,
300 MHz): d = 0.88 (t, J = 6.8 Hz, 3H, –CH2CH3),
0.92 (d, J = 6.3 Hz, 3H, –CH(CH3)–), 1.15–1.40 (m,
34H, 17 · –CH2–), 1.49 (d, J = 6.9 Hz, 3H, –NH-
CH(CH3)Ph), 1.85–2.25 (m, 7H, –CH2CH@CHCH2,
–CH–, –CH(CH3)CH2CONH–), 5.16 (qd, J = 7.5,
7.2 Hz, 1H, NHCH(CH3)Ph), 5.35 (t, J = 4.8 Hz,
2H, –CH@CH–), 5.61 (br d, J = 7.5 Hz, 1H, –NH-
CH(CH3)Ph); 13C NMR (CDCl3, 75 MHz): d = 171.6
(–C@O), 143.2, 129.9, 128.6, 127.3, 126.2 (C@C, –Ph),