10416
M. Avi et al. / Tetrahedron 60 (2004) 10411–10418
d: 212.90 (CO); 48.33 (C4); 39.17 (C5); 37.28 (C2); 21.81
(CH3).
citric acid. After addition of freshly generated HCN
(2 equiv),13 the mixture was stirred at room temperature
until quantitative conversion. The emulsion was broken
with Celite 545, filtered and dried over Na2SO4. Evapor-
ation of the solvent yielded the crude cyanohydrins. NMR
data of compounds 3, 4 and 6 are given above (compounds 5
and 7 are unstable).
4.2.6. General procedure for the synthesis of racemic
cyanohydrins. To a solution of ketone in TBME (tert-butyl
methyl ether), weakly basic ion-exchange resin (Amberlyst
A-21) and freshly generated HCN (2 equiv)13 were added.
The mixture was stirred at room temperature, and after
quantitative conversion (5–24 h), the mixture was filtered
over a bed of Na2SO4. Evaporation of the solvent yielded
the crude cyanohydrins. Structures were confirmed by NMR
analysis. NMR data of compounds 3, 4 and 6 are given
below (compounds 5 and 7 are unstable).
4.2.9. Synthesis of acetoxycarbonitriles. According to
standard procedures, the cyanohydrins were acetylated with
1.5 equiv acetic anhydride and 1.1 equiv pyridine in
CH2Cl2. NMR and MS data of compounds 8b–12 are
given below.
4.2.6.1.
3-Hydroxy-2-methyltetrahydrofuran-3-
4.2.9.1. 3-Acetoxy-2-methyltetrahydrofuran-3-carbo-
nitrile (8b, 9b). 1H NMR (200 MHz, CDCl3) d: 4.2–3.8 (m,
3H, H2, H5, H50); 2.80–2.40 (m, 2H, H4, H40); 2.26 (s, 3H,
Ac–CH3 trans); 2.16 (s, 3H, Ac–CH3 cis); 1.53 (d, 3H, CH3
cis, JZ6.2 Hz); 1.4 (d, 3H, CH3 trans, JZ6.2 Hz). 13C
NMR (50 MHz, CDCl3) d: cis-8b, -9b: 169.34 (Ac–CO);
117.18 (CN); 82.28 (C3); 78.98 (C2); 65.99 (C5); 39.06
(C4); 20.95 (Ac–CH3); 17.50 (CH3); trans-8b, -9b: 169.24
(Ac–CO); 117.18 (CN); 82.19 (C3); 75.37 (C2); 66.04 (C5);
39.06 (C4); 21.01 (Ac–CH3); 13.48 (CH3). MS: 170 (MC);
153 (MKCH3); 143 (MKCN); 128 (MK(CNCCH3)); 110
(MKOAc); 101 (MK(CNCAc).
carbonitrile (3b, 4b). 1H NMR (200 MHz, CDCl3): d:
4.2–3.8 (m, 3H, H2, H5, H50); 3.8–3.2 (broad s, 1H, OH);
2.7–2.2 (m, 2H, H4, H40); 1.4 (d, 3H, CH3 cis, JZ6.2 Hz);
1.35 (d, 3H, CH3 trans, JZ6.2 Hz). 13C NMR (50 MHz,
CDCl3) d: cis-3b, -4b: 119.89 (CN); 83.25 (C3); 74.23 (C2);
65.99 (C5) 40.41 (C4); 17.36 (CH3); trans-3b, -4b: 119.89
(CN); 82.24 (C3); 72.63 (C2); 65.99 (C5); 40.86 (C4); 12.96
(CH3).
4.2.6.2. 3-Hydroxy-2-methyltetrahydrothiophen-3-
carbonitrile (3c, 4c). H NMR (200 MHz, CDCl3): d: cis-
1
3c,0-4c: 3.4 (q, 1H, H2, JZ6.830Hz); 3.1–2.9 (m, 2H, H5,
H5 ); 2.5–2.4 (m, 2H, H4, H4 ); 1.5 (d, 3H, CH3, JZ
6.83 Hz); trans-3c, -4c: 3.7 (q, 1H, H2, JZ6.83 Hz); 3.1–
2.9 (m, 2H, H5, H50); 2.60–2.55 (m, 1H, H4); 2.4–2.3 (m,
1H, H40); 1.4 (d, 3H, CH3, JZ6.83 Hz). 13C NMR
(125 MHz, CDCl3) d: cis-3c, -4c: 118.99 (CN); 79.68
(C3); 50.70 (C2); 40.88 (C4); 27.21 (C5); 13.84 (CH3);
trans-3c, -4c: 119.43 (CN); 75.91 (C3); 51.09 (C2); 42.47
(C4); 27.90 (C5); 19.77 (CH3).
4.2.9.2. 3-Acetoxy-2-methyltetrahydrothiophen-3-
carbonitrile. H NMR (500 MHz, CDCl3) d: cis-8c, -9c:
1
3.69 (q, 1H, H2, JZ6.84 Hz); 3.01–2.88 (m0, 2H, H5,H50);
2.9–2.8 (m, 1H, H4); 2.57–2.47 (m, 1H, H4 ); 2.14 (s, 3H,
Ac–CH3); 1.53 (d, 3H, CH3, JZ6.84 Hz); trans-8c, -9c:
3.88 (q, 1H, H2, JZ6.83 Hz); 3.01–2.88 (m0, 2H, H5,H50);
2.9–2.8 (m, 1H, H4); 2.57–2.47 (m, 1H, H4 ); 2.18 (s, 3H,
Ac–CH3); 1.38 (d, 3H, CH3, JZ6.84 Hz). 13C NMR
(125 MHz, CDCl3) d: cis-8c, -9c: 169.13 (Ac–CO);
115.69 (CN); 81.59 (C3); 48.26 (C2); 38.91 (C4); 27.15
(C5); 21.03 (Ac–CH3); 19.72 (CH3); trans-8c, -9c: 166.63
(Ac–CO); 117.15 (CN); 78.66 (C3); 48.97 (C2); 38.91 (C4);
26.54 (C5); 21.14 (Ac–CH3); 15.75 (CH3). MS: 186 (MC);
159 (MKCN); 144 (MK(CNCCH3)); 126 (MKOAc).
4.2.6.3. 3-Hydroxytetrahydrofuran-3-carbonitrile (6).
1H NMR (500 MHz, CDCl3): d: 4.09–4.01 (m, 3H, H5, H50,
H2, JZ6.83, 1.46 Hz); 3.99–3.96 (d, 1H, H20, JZ9.76 Hz);
2.52–2.45 (m, 1H, H4, JZ8.30, 5.37 Hz); 2.36–2.31 (m,
1H, H40, JZ4.39 Hz). 13C NMR (125 MHz, CDCl3) d:
120.09 (CN); 78.6 (C2); 71.95 (C3); 67.71 (C5); 41.10 (C4).
4.2.9.3. 3-Acetoxytetrahydro-2H-pyran-3-carbo-
nitrile (10). H NMR (500 MHz, CDCl3) d: 4.06 (d, 1H,
4.2.7. General procedure for the synthesis of the
cyanohydrins with HbHNL. To a solution of ketone in
TBME, an aqueous solution of HbHNL (700–1500 IU per
mmol ketone) was added and the resulting mixture was
stirred until an emulsion was formed. The enzyme was
previously diluted with distilled water (1/2 v/v) and the pH
was adjusted with 10% citric acid. After addition of freshly
generated HCN (2 equiv),13 the mixture was stirred at room
temperature until quantitative conversion. The emulsion
was broken with Celite 545, filtered and dried over Na2SO4.
Evaporation of the solvent yielded the crude cyanohydrins.
NMR data of compounds 3, 4 and 6 are given above
(compounds 5 and 7 are unstable).
1
H2, JZ12.2 Hz); 3.82–3.75 (m, 2H, H20, H6); 3.66–3.60
(m, 1H, H600, JZ5.8 Hz); 2.43–2.37 (m, 1H, H4); 2.15–2.09
(m, 1H, H4 ); 2.14 (s, 3H, Ac–CH3); 1.84 (m, 2H, H5, H50,
JZ5.8 Hz). 13C NMR (125 MHz, CDCl3) d: 168.91 (Ac–
CO); 117.41 (CN); 71.20 (C3); 68.94 (C2); 68.10 (C6);
32.86 (C4); 22.05 (Ac–CH3); 21.16 (C5). MS: 170 (MC);
143 (MKCN); 128 (MKAc); 110 (MKOAc); 101 (MK
(CNCAc).
4.2.9.4. 3-Acetoxytetrahydrofuran-3-carbonitrile
1
(11). H NMR (500 MHz, CDCl3) d: 4.25 (d, 1H, H2, JZ
10.7 Hz); 4.07 (d, 1H, H20, JZ10.7 Hz); 4.02–3.94 (m, 2H,
H5, H50, JZ5.37 Hz); 2.68–2.62 (m, 1H, H4, JZ6.35 Hz);
2.53–2.46 (m, 1H, H40, JZ6.35 Hz); 2.14 (s, 3H, Ac–CH3).
13C NMR (125 MHz, CDCl3) d: 169.50 (Ac–CO); 117.52
(CN); 77.06 (C3); 74.76 (C2); 67.40 (C5); 39.38 (C4); 20.92
(Ac–CH3). MS: 156 (MC); 129 (MKCN); 96 (MKOAc);
87 (MK(CNCAc).
4.2.8. General procedure for the synthesis of the
cyanohydrins with PaHNL. To a solution of ketone in
TBME, a solution of PaHNL (200–450 IU per mmol
ketone, TBME/enzyme 5/7 v/v) was added and the resulting
mixture was stirred until an emulsion was formed. The pH
of the enzyme solution was previously adjusted with 10%