A short total synthesis of (±)-isoafricanol and two of its isomers

Article abstract of DOI:10.1055/s-1998-1720

The syntheses of (±)-isoafricanol and two of its isomers were achieved from 2,5,5-trimethylcyclohex-2-en-1-ol. The key step was a photoreductive radical cyclisation of an unsaturated ketone.

Full text of DOI:10.1055/s-1998-1720

June 1998
SYNLETT
621
A Short Total Synthesis of (±)-Isoafricanol and Two of its Isomers
*
Janine Cossy , Samir BouzBouz, C. Mouza
Laboratoire de Chimie Organique, Associé au CNRS, ESPCI, 10 rue Vauquelin 75231 - Paris Cedex 05 - France
Fax: (33) 1 40 79 44 25. e-mail: janine.cossy@espci.fr
Received 26 January 1998
Abstract: The syntheses of (±)-isoafricanol and two of its isomers were
achieved from 2,5,5-trimethylcyclohex-2-en-1-ol. The key step was a
photoreductive radical cyclisation of an unsaturated ketone.
into (±)-isoafricanol as unique product in 72% yield. The chelotropic
addition occurred from the less hindered convex face that bears the
hydroxy group. The physical properties and spectroscopic data of (±)-
5
isoafricanol were in accordance with data published for the authentic
natural product.
The sesquiterpene africanol was isolated for the first time in 1974 from
1
the soft coral Lemnalia africana and its stereoisomer isoafricanol was
2
isolated in 1986 from Leptographium eundbergii Lag. and Mel.
Scheme 1
3
The first synthesis of (±)-africanol, reported in 1986, involved 25 steps
and featured a Claisen rearrangement to construct the hydroazulene
4
skeleton. A selective transannular cyclization of an epoxy humulene, as
5
well as an anionic oxy-Cope rearrangement, have also been employed
in alternative approaches leading to (±)-africanol. Furthermore, the
anionic oxy-Cope rearrangement has been used to synthesize (±)-
5
isoafricanol in 9 steps from 5,5-dimethylcyclohexan-1,3-dione.
A
reductive intramolecular radical cyclization has also been reported to
generate (+)-africanol and (+)-isoafricanol from (1R,2S,4S,8S)-4-
2,4
6
alkoxy-1,6,6-trimethyltricyclo[6.1.0.0 ]nonane. We report here a
short synthesis of (±)-isoafricanol and two of its isomers starting from
7
the 2,5,5-trimethylcyclohex-2-enol 1, that features a photoreductive
8
cyclization of the appropriate unsaturated ketone 5.
The synthesis of the required substituted cycloheptenone 4 was achieved
in
3 steps from 2,5,5-trimethylcyclohex-2-en-1-ol 1. When the
cyclopropylcarbinol 2, obtained from 1 (ZnEt , CH I ), was treated with
2
2 2
acetic acid (5 equiv.) and acetic anhydride (10 equiv.) at 120 °C, the
acetoxycyclohept-3-ene 3, resulting from
homoallyl rearrangement, was isolated in 90% yield. After
a cyclopropylcarbinyl/
9
saponification of the acetate (MeOH, K CO ) and oxidation of the
2
3
resulting alcohol with PCC (3 equiv.), the cycloheptenone 4 was isolated
in 85% yield. The enone 4 was alkylated regioselectively in DME by
quenching the corresponding potassium enolate (KH, 25 °C) with 1-
10
iodobut-3-ene. Cycloheptenone 5, was isolated in 67% yield. The
Scheme 2
hydroazulenol skeleton of (±)-isoafricanol was generated on irradiating
5 in the presence of Et N (10 equiv.) in acetonitrile (5 x 10 M) at 254
nm for 2 h. Products 6 (55%) and 7 (27%) were isolated after
purification by TLC. The relative configuration at the ring fusion of 6
and 7 was determined by comparison of the H NMR spectra in
which showed a slight upfield shift in
pyridine-d for the bridgehead hydrogen in the trans fused isomer (2.72
-2
3
11
(±)-Isoafricanol was obtained from 2,5,5-trimethylcyclohex-2-enol in 7
steps with an overall yield of 9%.
12
13
1
14
pyridine-d and CDCl
5
3
Acknowlegment: S. B. thanks the CNRS for a grant.
5
ppm versus 2.75 ppm) and a significant downfield shift for the cis
congener (3.12 ppm versus 2.77 ppm). The relative configuration of the
methyl group at C-5 and the hydroxy group at the bridgehead center (cis
References and Notes
(1) Tursch, B.; Braekman, J. C.; Daloze, D.; Fritz, P.; Kelecon, A.;
or trans) was based on the solvent effect on the chemical shift of the
Karlsson, R.; Losman, D. Tetrahedron Lett. 1974, 747-750.
15
methyl group between pyridine-d and CDCl . The cyclopropanation
5
3
of hydroazulenol
compounds 8a, 8b, whereas hydroazulenol 7 was cyclopropanated
6
afforded
a
1:1 mixture of two inseparable
(2) Abraham, W. R.; Ernest, L.; Witte, L.; Hanssen, H. P.; Sprecher, E.
16
Tetrahedron 1986, 42, 4475-4480.

622
LETTERS
SYNLETT
(3) a) Paquette, L. A.; Ham, W. H. Tetrahedron Lett. 1986, 27, 2341-
2344. b) Paquette, L. A.; Ham, W. H. J. Am. Chem. Soc. 1987,
109, 3025-3036.
3H); 0.93 (s, 3H); 1.30 (s, 3H); 1.87 (s, 3H); 1.01-2.33 (m, 10H);
13
2.75 (t, J = 9.5 Hz, 1H); 5.63-5.70 (m, 1H). C NMR (CDCl , 75
3
MHz) δ: 17.3 (q); 23.1 (q); 26.0 (t); 27.3 (q); 31.2 (s); 33.0 (t);
35.4 (q); 40.1 (t); 46.5 (d); 49.9 (d); 51.5 (t); 81.4 (s); 125.0 (d);
(4) Shirahama, H.; Hayano, K.; Kanemoto, Y.; Musimi, S.; Ohtsuka,
T.; Hashiba, N.; Furusaki, A.; Murata, S.; Noyori, R.; Matsumoto,
T. Tetrahedron Lett. 1980, 21, 4835-4838.
13
139.2 (s). C NMR (pyridine-d ) δ: 18.3 (q); 23.8 (q); 26.8 (t);
5
27.3 (q); 31.8 (s),;33.2 (t); 35.7 (q); 40.7 (t); 49.1 (d); 49.5 (d);
52.2 (t); 80.9 (s); 124.1 (d); 139.8 (s). MS (EI, 70 eV): m/z 208
(4), 190 (92), 175 (100), 161 (47), 147 (45), 109 (61), 91 (39).
(5) Fan, W.; White, J. B. J. Org. Chem. 1993, 58, 3557-3562.
(6) Sugimura, T.; Futagawa, T.; Tai, A. Chem. Lett. 1990, 2295-2298.
-1
1
(13) Compound 7: IR (film): 3480, 2945, 1380, 1360 cm . H NMR
(7) Ellis, J. E.; Dutcher, J. S.; Heathcock, C. H. J. Org. Chem. 1976,
41, 2670-2676.
(CDCl , 300MHz) δ: 0.85 (s, 3H); 0.91 (d, J = 6.0 Hz, 3H); 1.05
3
(s, 3H); 1.75 (s, 3H); 1.20-2.01 (m, 9H); 2.20 (dd, J = 13.0, 7.5
(8) Belotti, D.; Cossy, J.; Pète, J. P.; Portella, C. J. Org. Chem. 1986,
51, 4196-4200.
1
Hz, 1H); 2.77 (t, J = 8.0 Hz, 1H); 5.50-5.56 (m, 1H). H NMR
(pyridine-d ) δ: 0.94 (s, 3H); 1.13 (d, J = 6.0 Hz, 3H); 1.30 (s,
5
(9) a) Sarel, S.; Yovell, J.; Sarel-Imber, M. Angew. Chem., Int. Ed.
Engl. 1968, 577-598. b) Vogel, P. in «Carbocation Chemistry»,
Elsevier, Amsterdam 1985.
3H); 1.75 (s, 3H); 1.38-2.01 (m, 9H); 2.50 (dd, J = 13.0, 7.5 Hz,
13
1H); 3.12 (t, J = 8.0 Hz, 1H); 5.60-5.68 (m, 1H). C NMR
(CDCl , 75 MHz) δ: 12.3 (q), 23.2 (q), 26.5 (t), 30.7 (q), 30.8 (t),
3
-1
1
(10) Compound 5: IR (film): 1700, 1665 cm . H NMR (CDCl ,
31.2 (s), 31.8 (q), 38.1 (t), 45.0 (d), 47.2 (t), 53.1 (d), 82.2 (s),
3
13
300MHz) δ: 0.92 (s, 6H); 1.81 (s, 3H); 1.90-2.15 (m, 6H); 2.55
122.7 (d), 139.1 (s). C NMR (pyridine-d ) δ: 13.4 (q); 23.6 (q);
5
(m, 2H); 2.95 (m, 1H); 4.97 (m, 2H); 5.63 (m, 1H); 5.80 (m, 1H).
27.1 (t); 31.2 (q); 31.5 (t); 31.7 (s); 32.4 (q); 38.7 (t); 46.0 (d);
47.6 (t); 54.4 (d); 81.5 (s); 123.4 (d); 139.8 (s). MS (EI, 70 eV): m/
z 208 (4), 190 (70), 175 (100), 161 (24), 147 (52), 109 (47), 91
(36).
13
C NMR (CDCl , 75 MHz) δ: 17.3 (q); 26.6 (t); 28.9 (q); 31.3
3
(t); 38.5 (t); 39.6 (t); 55.0 (t); 56.7 (d); 114.9 (t); 124.2 (d); 136.7
(s); 138.5 (d); 208.6 (s). MS (EI, 70 eV): m/z 206 (8); 191 (8); 165
(40); 137 (23); 109 (45); 95 (32); 81 (100).
(14) Demarco, P. V.; Farkas, E.; Doddrell, D.; Mylari, B. L.; Wenkert,
(11) Triethylamine (10 equiv.) was added to a degassed solution of 5
(0.40 g) in acetonitrile (40 mL). The solution was irradiated for 2
h at 254 nm in a merry-go-round apparatus equipped with 12 low
pressure mercury Philips TUV 15 lamps. Quartz tubes (10 mm
o.d.) were used.
E. J. Am. Chem. Soc. 1968, 90, 5480-5486.
(15) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974-
6981.
(16) Mass spectra of 8a and 8b were run on a GC/MS Hewlett-Packard
5890 (EI mode at 70eV). Compound 8a: MS m/z 222 (12); 207
(19); 189 (63); 165 (42); 109 (51); 67 (70); 55 (100); 53 (53).
Compound 8b: MS m/z 222 (7); 207 (30); 189 (30); 165 (89); 109
(64); 67 (57); 55 (100); 53 (53).
-1
1
(12) Compound 6: IR (film): 3480, 2945, 1380, 1360 cm . H NMR
(CDCl , 300MHz) δ: 0.92 (d, J = 6.5 Hz, 3H); 0.93 (s, 3H); 1.03
3
(s, 3H); 1.76 (s, 3H); 1.10-2.21 (m, 10H); 2.74 (t, J = 9.5 Hz, 1H);
1
5.63-5.70 (m, 1H). H NMR (pyridine-d ) δ: 0.91 (d, J = 7.5 Hz,
5