F. Benedetti et al. / Tetrahedron: Asymmetry 12 (2001) 505–511
509
meter. TLCs were performed on Polygram® Sil G/
UV254 silica gel pre-coated plastic sheets (eluant: light
petroleum–ethyl acetate). Flash chromatography was
run on silica gel 230–400 mesh ASTM (Kieselgel 60,
Merck). Light petroleum refers to the fraction with bp
40–70°C and ether to diethyl ether.
chromatography. The first product was evaporated to
afford trans-4,5-dihydro-4-methyl-5-pentyl-2(3H)-fura-
none 4. All spectroscopic data are in accordance with
those reported in the literature.24 The second band to
elute was evaporated to afford cis-4,5-dihydro-4-
methyl-5-pentyl-2(3H)-furanone 3. IR (neat), cm−1:
1779 (O-CꢀO), 1212 (C-O); m/z: 170 (1), 101 (17), 99
(100), 83 (24), 71 (35), 70 (14), 56 (20), 55 (26), 43 (44),
4.2. Substrate synthesis
1
42 (44), 41 (32). H and 13C NMR data are in accor-
4.2.1. Ethyl 3-methyl-4-oxononanoate 5.9 A mixture of
ethyl crotonate (11.5 g, 0.1 mol) and hexanal (60.1 g,
0.6 mol) was heated at 80°C under N2 in the presence
of benzoyl peroxide (2.0 g, 80 mmol) for 9 h. Three
further portions of benzoyl peroxide (2.0 g, 80 mmol)
were added to the mixture regularly. The crude reaction
mixture was then washed with saturated NaHCO3 and
the ketoester 5 was purified by flash chromatography
(eluent: light petroleum–ether, gradient from 98:2 to
90:10). Oil. IR (neat), cm−1: 1735 (O-CꢀO), 1715 (CꢀO,
dance with the literature.12
4.2.4. Synthesis of methyl 3-methyl-4-oxononanoate 7.18
The acid 6 (0.100 g, 0.54 mmol) was esterified with
diazomethane to give the title compound 7. IR (neat),
cm−1: 1735 (O-CꢀO), 1715 (CꢀO), 1187 (C-O); 1H
NMR, l, ppm: 0.87 (3H, t, J=6.8 Hz, CH3), 1.12 (3H,
d, CH3CH), 1.31 (4H, m, (CH2)2), 1.57 (2H, quintet,
J1=J2=J3=7.3 Hz, CH2), 2.26 (1H, dd, J=17.0 and
8.8 Hz, H-2), 2.50 (2H, m, CH2), 2.75 (1H, dd, J=17.0,
5.7 Hz, H-2), 2.98 (1H, m, H-3), 4.08 (3H, s, CH3); 13C
NMR, l, ppm: 13.9 (q), 16.6 (q, CH3CH), 22.4 (t), 23.2
(t), 31.2 (t), 36.6 (t, C-2), 41.0 (t, C-5), 41.9 (d, C-3),
51.6 (q, CH3), 172.8 (s, O-CꢀO), 213.0 (s, CꢀO).
1
sh), 1187 (C-O); H NMR, l, ppm: 0.87 (3H, t, CH3),
1.12 (3H, d, J 6.8 Hz, CH3CH), 1.31 (7H, m, (CH2)2
and CH3CH2O), 1.57 (2H, quintet, J1=J2=J3=7.3 Hz,
CH2), 2.26 (1H, dd, J=17.0, 8.8 Hz, H-2), 2.50 (2H, m,
CH2), 2.75 (1H, dd, J=17.0, 5.7 Hz, H-2), 2.98 (1H, m,
H-3), 4.08 (2H, q, CH2O); 13C NMR, l, ppm: 13.9 (q),
14.1 (q, CH3CH), 16.7 (q, CH3CH2O), 22.4 (t), 23.2 (t),
31.2 (t), 37.4 (t, C-5), 41.7 (t, C-2), 41.9 (d, C-3), 60.4 (t,
CH2O), 172.3 (s, C-1), 213.0 (s, C-4); m/z: 169 (33), 158
(32), 142 (16), 115 (25), 112 (37), 99 (100), 71 (78), 43
(92).
4.3. General procedure for baker’s yeast reductions
Method A: To a stirred suspension of raw baker’s yeast
(56 g) in phosphate buffer (0.1 M, pH 7.4, 500 mL) was
added glucose (56 g); the suspension was stirred for 30
min and the 4-keto ester 5 or 4-ketoacid 6 (1.8 mmol)
was added at room temperature. The reaction was
monitored by HRGC. At the end of the reaction, brine
was added and the broth was continuously extracted
with ether for 48 h. The organic phase was dried and
evaporated.
4.2.2. 3-Methyl-4-oxononanoic acid 6.18 A mixture of
ketoester 5 (0.490 g, 2.29 mmol) and 90% KOH in
methanol (3.7 mL, 4.6 mmol) was stirred at room
temperature for two days. After evaporation of the
solvent, water was added and the mixture acidified with
HCl. The mixture was extracted with diethyl ether and
the organic extract dried over Na2SO4, filtered and the
filtrate evaporated to afford acid 6 as a colourless oil
(0.417 g, 98%). IR (neat), cm−1: 3150 (OH), 1740 (O-
Method B: To a stirred suspension of dry baker’s yeast
purchased from Sigma Aldrich (2.8 g) in water (19 mL)
was added glucose (3.1 g); the suspension was stirred
for 30 min and the 4-keto ester 5 or 4-ketoacid 6 (0.5
mmol) was added at room temperature. The reaction
was monitored by HRGC. At the end of the reaction,
brine was added and the broth was continuously
extracted with ether for 48 h. The organic phase was
dried and evaporated.
1
CꢀO), 1715 (CꢀO), 1280 (C-O); H NMR, l, ppm: 0.87
(3H, t, CH3), 1.14 (3H, d, J=7.3 Hz, CH3CH), 1.23–
1.34 (4H, m, (CH2)2), 1.57 (2H, quintet, J1=J2=J3=
7.3 Hz), 2.32 (1H, dd, J=17.0, 5.4 Hz, H-2), 2.50 (2H,
m, 2 H-5), 2.81 (1H, dd, J=17.0, 8.9 Hz, H-2), 2.96
(1H, m, H-3), 10.0 (1 H, br s, OH); 13C NMR, l, ppm:
13.9 (q), 16.6 (q), 22.4 (t), 23.2 (t), 31.3 (t), 36.6 (t, C-5),
41.0 (t, C-2), 41.7 (d), 178.3 (s, C-1), 213.0 (s, C-4);
m/z: 130 (15), 115 (11), 112 (15), 99 (82), 71 (56), 43
(100).
Method C: To a stirred suspension of raw baker’s yeast
(5 g) in water (10 mL) at room temperature was added
the 4-keto ester 5 or the 4-ketoacid 6 (0.5 mmol). The
course of the reaction was monitored by HRGC. At the
end of the reaction, brine was added and the broth was
continuously extracted with ether for 48 h. The organic
phase was dried and evaporated.
4.2.3. Synthesis of the lactones 3 and 4.9 To a solution of
the ketoester 5 (3.85 g, 18 mmol) in methanol (5 mL)
was added solid NaOH (0.78 g, 19.5 mmol) and the
mixture stirred at room temperature for 3 h. After
evaporation of the solvent, 1N NaOH (1.8 mL) was
added and the mixture was heated at 50°C. Sodium
borohydride (0.680 g, 18 mmol) in 0.1N NaOH (7.6
mL) was added dropwise. At the end of the reaction the
mixture was acidified with concentrated HCl and
heated for a further two hours. After the usual work-up
a 1:1 mixture of the two diastereomers 3 and 4 was
obtained in 68% yield, which were separated by flash
4.3.1. Baker’s yeast reduction of the ketoester 5. The
reaction was carried out on ketoester 5 (0.642 g, 3
mmol) according to method C. Since the reaction
stopped at low conversion values additional raw bak-
er’s yeast (15 g) in water (20 mL) was added. The
reaction was extracted after 31 days. The organic phase
was dried and evaporated. Separation by flash chro-
matography (eluent: gradient of petroleum ether–ethyl
acetate from 0% up to 3%) afforded the lactone cis-