Formal total synthesis of (±)-occidol

Article abstract of DOI:10.1080/00397910600775663

The conversion of tetralone 1 to methylketone 7, a valuable intermediate of occidol 8, has been accomplished in four steps (reduction, mesylation, cyanation, and Grignard reaction with methylmagnesium bromide). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600775663

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Formal Total Synthesis of (±)‐Occidol
a
a
William J. Vera & Ajoy K. Banerjee
a
Centro de Química, Instituto Venezolano de Investigaciones Cientificas
IVIC), Caracas, Venezuela
(
Version of record first published: 16 Feb 2007.
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Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications , 36: 3091–3094, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600775663
Formal Total Synthesis of (+)-Occidol
William J. Vera and Ajoy K. Banerjee
Centro de Qu ´ı mica, Instituto Venezolano de Investigaciones Cientificas
(
IVIC), Caracas, Venezuela
Abstract: The conversion of tetralone 1 to methylketone 7, a valuable intermediate of
occidol 8, has been accomplished in four steps (reduction, mesylation, cyanation, and
Grignard reaction with methylmagnesium bromide).
Keywords: Cyanation, Grignard reaction, occidol, tetralones
[1]
Occidol 8, a principal constituent of essential oil of Thuja species, belongs
to the eudesmane class of sesquiterpenes. Several syntheses of occidol 8 have
[2]
been accomplished by a variety of methods. In some of these approaches,
substituted a-tetralones have been smoothly converted to occidol 8. To
date, no attempt has been made to synthesize occidol from substituted
[
3]
b-tetralones. The recently reported 5,8-dimethyl b-tetralone 1 prompted
us to study its conversion to occidol 8.
Tetralone 1 was reduced with sodium borohydride to an oily alcohol 2,
which was converted to its mesylate derivative 3 by adopting standard
procedures. The conversion to the nitrile derivative was accomplished by
[
4]
heating with sodium cyanide and hexamethyl-phosphoramide. The nitrile
4
was formed along with products 5 and 6.
Received in U.S.A. March 9, 2006
Address correspondence to Ajoy K. Banerjee, Centro de Qu ´ı mica, Instituto
Venezolano de Investigaciones Cientificas (IVIC), Apartado 21827, Caracas, 1020,
Venezuela. E-mail: abanerje@ivic.ve
3
091

3
092
W. J. Vera and A. K. Banerjee
The separation of 4 from the reaction mixture by silica-gel chromato-
graphy was successful; however, compounds 5 and 6 could not be separated
because of their close Rf values. The nitrile 4, on heating with methylmagne-
sium bromide in ether (3M) at 508C for 72 h, produced methylketone 7 in
1
[2]
80%. The IR and H NMR spectral data compared to literature values
confirmed the assigned structure. The one-step conversion of 7 to occidol 8
[
2]
has already been reported, so this synthesis constitutes the formal total
synthesis of 8.
EXPERIMENTAL
1
Unless otherwise stated, IR spectra were taken on Nicolet FT instrument. H
1
and C NMR spectra were recorded on Brucker AM 300-MHz instrument in
3
CDCl . Mass spectra were run on gas chromatograph Hewlett Packard 5890
3
Quadrupolar 5972 Series S. Melting points were recorded on an

Formal Total Synthesis of (+)-Occidol
3093
electrothermal melting-point apparatus. The solution is diluted with water,
extracted with ether, washed with brine, dried (MgSO ), and evaporated
4
under reduced pressure. Column chromatography was performed on silica
gel (Merck grade 60, 70–230 mesh). The spectral and analytical data of all
new compounds have been reported in the Experimental section. Micro-
analyses were carried out at the Chemistry Department, IVIC, Caracas.
5
,8-Dimethyl-1,2,3,4-tetrahydro-2-naphthol 2
Sodium borohydride (980 mg, 26 mmol) in ethanol (70 mL) was added to a
solution of 1 (2.26 g, 13 mmol) in ethanol (70 mL). The mixture was stirred
for 2 h at room temperature, decomposed with acetic acid, diluted with
water, and extracted with diethyl ether. The organic layer was washed,
dried, and purified on silica gel (hexane–diethyl ether 4:6) to obtain 2
þ
þ
21
(
2.17 g, 95%); m/z 176 (M ) and 158 (M -H O); n
2
3375 cm (OH);
max
1
H: d 1.85–1.78 (m, 2H, CH ), 2.21 (s, 3H, C5-Me), 2.26 (s, 3H, C8-Me),
2
3
C-6) and 6.84 (bs, 1H, C-7); C: d 136.7 (C-10), 135 (C-9), 130.5 (C-8),
.1–2.5 (m, 4H, C1-2H, C4-2H), 4.13–4.10 (m, 1H, CHOH), 6.79 (bs, 1H,
1
3
1
2
29.6 (C-5), 128.3 (C-6), 126.8 (C-7), 67.8 (C-2), 35.6 (C-1), 31.4 (C-3),
7.5 (C-4), 19.4 (C-12) and 19.2 (C-11). (Found: C, 82.15; H, 9.37.
C H O requires C, 81.77%; H, 9.15%.)
12 16
5
,8-Dimethyl-1,2,3,4-tetrahydro-2-cyanonaphthalene 4
Mesylchloride (1.2 mL, 14.5 mmol) was added to a solution of 2 (2.17 g,
2.3 mmol) in pyridine (12 mL). The resulting brown solution was stirred at
1
room temperature for 24 h, diluted with water, and extracted with ether.
The organic extract was washed with a 5% solution of copper sulfate,
washed with brine, dried, and evaporated to give 3 (2.41 gr, 77%); m/z 254
þ þ þ
M ), 175 (M -MeSO ) and 158 (M -MeSO OH); H: d 2.15–2.22
2 2
1
(
(
(
(
m, 2H, CH ), 2.26 (s, 3H), 2.33 (s, 3H) (C-5, C-8), 2.81–3.03 (m, 4H)
2
C-1 and C-4), 3.09 (s, 3H, MeSO ), 5.16–5.28 (m, 1H, CHOSO Me), 6.86
3
2
1
bs, 1H), and 6.92 (bs, 1H) (C-6 and C-7); C: d 136.5 (C-10), 135.5 (C-9),
3
1
3
30.2 (C-8), 129.7 (C-5), 128.7 (C-6), 126.9 (C-7), 78.5 (C-2), 38.7 (C-13),
3.5 (C-3), 28.9 (C-1), 26.4 (C-4), 19.4 (C-12) and 19.3 (C-11).
The mesylate 3 (2.0 g, 7.9 mmol), powdered sodium cyanide (1.16 g,
3.7 mmol), and hexamethylphosphoramide (28 mL) was heated at 1208C
2
for 72 h under argon. The reaction mixture was diluted with water,
extracted with ether, dried and evaporated. The resulting material was
purified on silica gel by eluting with hexane to afford a mixture of 5 and 6
þ
þ
(
641 mg, 38%); m/z 158 (M ) and 156 (M ).
Further elution (hexane–diethyl ether 8:2) yielded 4 (521 mg, 36%),
þ
þ
þ
mp 107–1108C; m/z 185 (M ), 170 (M -Me), 158 (M -HCN) and 143

3
094
W. J. Vera and A. K. Banerjee
2234 cm (CN); H: d 1.99–2.07 (m, 2H, CH ), 2.21
s, 3H), 2.28 (s, 3H) (C-5 and C-8), 2.77–3.06 (m, 5H) (C-1, C-4 and
þ
21
1
(
M -HCN-Me); n
max
2
(
1
3
CHCN), 6.80 (bs, 1H), 6.87 (bs, 1H); (aromatic protons) C: d 136.3
C-10), 135.8 (C-9), 134.3 (C-8), 128.7 (C-6), 127.9 (C-5), 127.3 (C-7),
22.3 (C-13), 29.6 (C-1), 27.6 (C-3), 25.9 (C-2), 20.7 (C-12), 19.3 (C-11).
Found: C, 84.68; H, 8.38. C H N requires C, 84.32%; H, 8.10%.)
(
1
(
1
3 15
5,8-Dimethyl-1,2,3,4-tetrahydro-2-naphthyl-ethan-l-one 7
A solution of methylmagnesium bromide in dry ether (1.8 mL, 3M) was added
dropwise to a solution of 4 (502 mg, 2.7 mmol) in tetrahydrofuran (11 mL).
The reaction mixture was heated at 508C for 72 h, and then hydrochloric
acid (10%) was cautiously added and extracted with ether. The organic
extract was washed, dried, evaporated, and chromatographed on silica gel
þ
(
(
(
(
(
hexane–diethyl ether 8 : 2) to obtain 7 (441 mg, 80%); m/z 202 (M ); 187
21
þ
þ
1
(CO); H: 1.81–1.71
M -Me), 144 (M -Me-COMe); n
m, 2H, CH ), 2.23 (s, 3H, MeCO) 2.28 (s, 6H; Me), 2.91–2.73 (m, 5H)
1708 cm
max
2
1
C-1, C-2, and C-4), 6.81 (bs, 1H, Ar-H), 6.86 (bs, 1H, Ar-H); C: d 211.3
3
C-13), 136.5 (C-10), 135.5 (C-9), 134.9 (C-8), 134.1 (C-5), 128.4 (C-6),
127.1 (C-7), 48.4 (C-2), 29.4 (C-3), 28.1 (C-14), 27.8 (C-1), 25.2 (C-4),
19.4 (C-12) and 19.2 (C-11). (Found: C, 83.38; H, 9.15. C H O requires
C, 83.12%; H, 8.97%.)
1
4 18
REFERENCES
1
. Reddy, P. A.; Rao, G. S. K. A simple synthesis of methyl 5,8-dimethyl-1,2,3,4-tetra-
hydro-2-naphthoate and its conversion into (+)-occidol. Ind. J. Chem. 1980, 19B,
53.
7
2
. Mane, R. B.; Kadam, A. J. A new synthesis of occidol. Collect. Czech. Chem.
Commun. 1999, 64, 527.
3
. Banerjee, A. K.; Vera, W.; Laya, M. S. A new synthesis of 5,8-dimethyl-2-
tetralone—a potential intermediate for the synthesis of ring A aromatic sesquiter-
penes: Novel transformation during acetoxylation of 5,8-dimethyldihydronaphtha-
lene. Synth. Commun. 2004, 34, 2301.
4
. Shaw, J. E.; Hsia, D. Y.; Parries, G. S.; Sawyer, T. K. Reaction of alkali metal
cyanides with alkyl halides in HMPA or HMPA containing crown ether. J. Org.
Chem. 1978, 43, 1017.