PAPER
Synthesis of Isoaminile Mediated by Enzymes
1153
(E,S)-3-Isopropyl-3-phenyl-4-hexenoic Acid [(E,S)-7]
(E,R)-Isopropyl-4-phenyl-5-hepten-2-one [(E,R)-8]
The ketone (E,R)-8 was obtained following the same procedure as
used for the synthesis of (E,S)-8.
Selected data for (E,R)-8; [a]D20 = –62.5.
To a solution of (E,R)-5 (46 g, 0.24 mol) in triethylorthoacetate
(TEOA; 0.6 L) placed in a 1 L round bottom flask equipped with a
condenser/distillation head was added propionic acid (1 mL). The
reaction mixture was heated to 150 °C and the EtOH was continu-
ously collected. During the reaction, propionic acid was occasional-
ly renewed. After 6–7 h the excess of TEOA was removed by
distillation to yield an orange-colored oily residue. To a solution of
the residue in EtOH–H2O (0.5 L, 1:2) was added dropwise a solu-
tion of KOH (22 g, 0.39 mol) in H2O (100 mL) and refluxed for 6
h. Most of TEOA was removed under reduce pressure and the resi-
due was washed with Et2O (2 × 200 mL) and dried over Na2SO4.
The water solution was neutralized with HCl (1 M) and washed with
CH2Cl2 (3 × 300 mL). The combined organic layers were dried over
Na2SO4 and the solvent was removed under reduced pressure to
give a yellow oil that was passed on a pad of silica gel using hex-
ane–EtOAc (9:1) as eluent affording compound (E,S)-7; yield: 50.1
g (90%); colorless oil; [a]D20 = +48.5 (c = 1.0, CHCl3).
1H NMR: d = 8.65 (br s, 1 H, CO2H), 7.35–7.06 (m, 5 H, ArH), 5.72
(dd, J = 15.4, 1.4 Hz, 1 H, CH=CHCH3), 5.56 (m, 1 H,
CH=CHCH3), 2.81–2.64 (m, 2 × 1 H, CH2), 2.48 [septuplet, J = 6.9
Hz, 1 H, CH(CH3)2], 1.82 (dd, J = 1.5, 5.5 Hz, 3 H, =CHCH3), 0.84
(d, J = 6.9 Hz, 3 H, CHCH3), 0.76 (d, J = 6.9 Hz, 3 H, CHCH3).
13C NMR: d = 177.9, 144.8, 133.7, 128.6, 128.5, 126.7, 126.5, 50.2,
43.1, 34.4, 32.8, 19.1, 18.7, 18.5.
Anal. Calcd for C16H22O (230.35): C, 83.43; H, 9.68. Found: C,
83.46; H, 9.64.
(E,2RS,4S)-Isopropyl-4-phenyl-5-hepten-2-ol [(E,2RS,4S)-9]
To an ice-cooled solution of (E,S)-8 (29.7 g, 0.13 mol) in EtOH (0.3
L) was added NaBH4 (7.6 g, 0.2 mol). After 4 h at r.t. the reaction
mixture was quenched with sat. NH4Cl (0.3 L), neutralized with
HCl (1 M) and washed with CH2Cl2 (3 × 300 mL). The combined
organic layers was dried over Na2SO4 and the solvent was removed
under reduced pressure to give the alcohol (E,2RS,4S)-9; yield: 24.8
g (83%); yellow pale oil.
1H NMR: d = 7.35–7.08 (m, 2 × 5 H, ArH), 5.68–5.83 (m, 2 × 1 H,
CH=CHCH3), 5.53–5.41 (m, 2 × 1 H, CH=CHCH3), 3.81–3.58 (m,
1 H, CHOH), 3.68–3.48 (m, 1 H, CHOH), 2.38–2.25 [m, 2 × 1 H,
CH(CH3)2], 2.14 (dd, J = 1.4, 13.3 Hz, 1 H, CHCHOH), 2.04 (dd,
J = 7.4, 14.8 Hz, 1 H, CHCHOH), 1.82 (m, 1 H, 2 × 3 H, CHCHOH,
=CHCH3), 1.75 (dd, J = 7.9, 14.9 Hz, 1 H, CHCHOH), 1.30 (br s, 1
H, OH), 1.18 (br s, 1 H, OH), 1.08 (d, J = 6.4 Hz, 3 H, OHCHCH3),
0.96 (d, J = 6.4 Hz, 3 H, OHCHCH3), 0.97–0.81 (m, 2 × 3 H,
CHCH3), 0.74 (d, J = 6.9 Hz, 3 H, CHCH3), 0.71 (d, J = 6.9 Hz, 3
H, CHCH3).
GC–MS (tR = 21.63 min): m/z = 232 (2) [M+], 189 (20), 143 (25).
13C NMR: d = 146.1, 145.8, 134.7, 133.6, 129.0, 128.8, 128.6,
128.5, 127.2, 126.9, 126.7, 126.5, 66.0, 65.9, 51.0, 50.8, 48.01,
47.7, 36.2, 36.2, 25.0, 24.9, 19.2, 19.16, 18.9, 18.7, 18.5, 18.4.
Anal. Calcd for C15H20O2 (232.33): C, 77.55; H, 8.68. Found: C,
77.66; H, 8.49.
GC–MS (tR = 20.36 min): m/z = 232 (2) [M+], 189 (10), 145 (100),
129 (15).
(E,R)-3-Isopropyl-3-phenyl-4-hexenoic Acid [(E,R)-7]
The acid (E,R)-7 was obtained following the same procedure as
used for the synthesis of (E,S)-7.
[a]D20 = –45.6.
(E,2RS,4R)-Isopropyl-4-phenyl-5-hepten-2-ol [(E,2RS,4R)-9]
The alcohols (E,2RS,4R)-9 were obtained following the same pro-
cedure used for the synthesis of (E,2RS,4S)-9.
Anal. Calcd for C15H20O2 (232.33): C, 77.55; H, 8.68. Found: C,
77.71; H, 8.53.
(E,1RS,3S)-Acetic Acid 3-Isopropyl-1-methyl-4-hexenyl Ester
[(E,1RS,3S)-10]
To a solution of alcohols (E,2RS,4S)-9 (16.2 g, 0.07 mol) in pyri-
dine (100 mL) was added Ac2O (20 mL). The reaction mixture after
12 h was worked in the usual way to afford the acetates (E,1R,3RS)-
10 which was used without further purification for the next step;
yield: 19.0 g (99%); yellow oil.
1H NMR: d = 7.34–7.04 (m, 2 × 5 H, ArH), 5.71–5.40 (m, 3 × 1 H,
CHOAc, CH=CHCH3), 4.87–4.71 (m, 1 H, CHOAc), 2.44–2.21 [m,
2 × 1 H, CH(CH3)2], 2.05 (dd, J = 7.8, 14.9 Hz, 1 H, CHCHOAc),
1.96 (dd, J = 1.7, 14.9 Hz, 1 H, CHCHOAc), 1.88–1.79 (m, 2 × 1 H,
2 × 3, CHCHOAc, =CCH3), 1.73 (s, 3 H, COCH3), 1.52 (s, 3 H,
COCH3), 1.06 (d, J = 6.3 Hz, 3 H, AcOCHCH3), 0.95 (d, J = 6.4 Hz,
3 H, AcOCHCH3), 0.87 (d, J = 6.6 Hz, 3 H, CHCH3), 0.83 (d, J =
6.6 Hz, 3 H, CHCH3), 0.77 (d, J = 6.9 Hz, 3 H, CHCH3), 0.69 (d,
J = 6.9 Hz, 3 H, CHCH3).
(E,S)-Isopropyl-4-phenyl-5-hepten-2-one [(E,S)-8]
To an ice-cooled solution of (E,S)-7 (38.9 g, 0.17 mol) and Et3N
(27.8 mL, 0.2 mol) in THF (0.3 L) was added dropwise a solution
of chloroethyl formiate (19.2 mL, 0.2 mol) over 30 min. After 1 h
the reaction mixture was concentrated under reduced pressure. The
residue was triturated in Et2O (200 mL) and the white solid was fil-
tered. To this solution at –15 °C was added dropwise under a N2 at-
mosphere a freshly prepared solution of MeMgI (Mg: 6.0 g, 0.25
mol, and MeI: 28.4 mL, 0.20 mol). After 1 h the reaction was
quenched with NH4Cl (sat., 0.3 L), neutralized with HCl (0.1 N),
washed with Et2O (2 × 0.2 L) and dried over Na2SO4. The solvent
was removed under reduced pressure to give an oil. Column chro-
matography of the crude with hexane–EtOAc (9:1) as eluent gave
compound (E,S)-8; yield: 27.4 g (70%), colorless oil; [a]D20 = +67.9
(c = 1.1, CHCl3).
1H NMR: d = 7.34–7.09 (m, 5 H, ArH), 5.72 (dd, J = 15.6, 1.0 Hz,
1 H, CH=CHCH3), 5.63–5.46 (m, 1 H, CH=CHCH3), 2.86 (s, 2 H,
CH2), 2.48 [septuplet, J = 6.9 Hz, 1 H, CH(CH3)2], 1.82 (dd, J = 1.2,
6.0 Hz, 3 H, =CHCH3), 1.63 (s, 3 H, COCH3), 0.87 (d, J = 6.9 Hz,
3 H, CHCH3), 0.75 (d, J = 6.9 Hz, 3 H, CHCH3).
13C NMR: d = 209.1, 145.4, 133.8, 128.6, 128.5, 126.7, 126.5,
126.4, 51.7, 50.7, 34.3, 32.8, 19.1, 18.7, 18.5.
13C NMR: d = 170.1, 145.0, 144.9, 133.6, 132.9, 128.2, 128.1,
127.8, 127.7, 125.8, 125.7, 125.5, 125.4, 68.4, 50.1, 49.8, 43.9,
43.6, 35.0, 33.8, 21.9, 21.8, 21.2, 20.6, 18.3, 17.8, 17.7.
GC–MS [tR = 21.57 min (I diast.)]: m/z = 230 (5) [M – 44], 171
(100), 143 (20).
GC–MS [tR = 21.65 min (II diast.)]: m/z = 230 (10) [M – 44], 171
(100), 143 (20).
GC–MS (tR = 20.31 min): m/z = 230 (2) [M+], 187 (100), 145 (90),
129 (80).
(E,1RS,3S)-Acetic Acid 3-Isopropyl-1-methyl-4-hexenyl Ester
[(E,1RS,3R)-10]
The esters (E,1RS,3R)-10 were obtained following the same proce-
dure as used for the synthesis of (E,1RS,3S)-10.
Anal. Calcd for C16H22O (230.35): C, 83.43; H, 9.68. Found: C,
83.56; H, 9.59.
Synthesis 2005, No. 7, 1148–1156 © Thieme Stuttgart · New York