Straightforward synthesis of the strong ambergris odorant γ-bicyclohomofarnesal and its endo-isomer from R-(+)-sclareolide

Article abstract of DOI:10.1016/S0040-4039(02)01392-8

γ-Bicyclohomofarnesal 1 and its endo isomer 5 were prepared in 47 and 26% overall yields, respectively, from commercial R-(+)-sclareolide (7), in a three-step sequence. The synthetic procedure involves the preparation of Weinreb's amide 9, dehydration of tertiary alcohol to form compounds 10 and 11, chromatographic separation and reduction with LiAlH₄. This approach is simple and can compete with the syntheses previously reported for the preparation of these important compounds, both in overall yields and in the number of synthetic steps.

Full text of DOI:10.1016/S0040-4039(02)01392-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6351–6353
Straightforward synthesis of the strong ambergris odorant
g-bicyclohomofarnesal and its endo-isomer from
R-(+)-sclareolide
Mar´ıa C. de la Torre,a,* Isabel Garc´ıaa and Miguel A. Sierrab
aInstituto de Qu´ımica Orga´nica, Consejo Superior de Investigaciones Cient´ıficas (CSIC), Juan de la Cierva 3, 28006 Madrid,
Spain
bDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad Complutense, 28040 Madrid, Spain
Received 19 April 2002; accepted 8 July 2002
Abstract—g-Bicyclohomofarnesal 1 and its endo isomer 5 were prepared in 47 and 26% overall yields, respectively, from
commercial R-(+)-sclareolide (7), in a three-step sequence. The synthetic procedure involves the preparation of Weinreb’s amide
9, dehydration of tertiary alcohol to form compounds 10 and 11, chromatographic separation and reduction with LiAlH4. This
approach is simple and can compete with the syntheses previously reported for the preparation of these important compounds,
both in overall yields and in the number of synthetic steps. © 2002 Elsevier Science Ltd. All rights reserved.
g-Bicyclohomofarnesal (Ambral® 1) is a strong amber-
ongoing project directed towards the synthesis of differ-
gris odorant with fine tonality.1 Apart from its value as
odorant, aldehyde 1 is a very versatile synthetic inter-
mediate. In fact, it has been converted in a four-step
sequence into (−)-Ambrox® (2),2 the commercially more
important amber chemical. Additionally, g-bicyclohomo-
farnesal (1) is a key intermediate in the preparation of
other terpene derivatives like (E)-dinorlabdadienal 33
and (+)-galanolactone 4.4 Furthermore, compound 5,
an isomer of g-bicyclohomofarnesal (1) having an endo-
double bond, has been prepared recently, and it has
been used as the key intermediate in the synthesis of
coscinosulfate 6, a selective inhibitor of Cdc25 protein
phosphatase (Fig. 1).5
ent types of terpenes,13 aldehyde 5 was required. To
prepare this compound, we followed the procedure
Because of its synthetic and commercial relevance, the
synthesis of aldehyde 1 has been repeatedly pursued,
and different approaches to this compound are known.
With the exception of the synthesis reported by Bar-
rero,6 who described an efficient entry to g-bicyclo-
homofarnesal from (−)-sclareol, the remaining ap-
proaches are inefficient linear multistep sequences.2,7–11
In clear contrast, there are only two reported syntheses
of pure aldehyde 5. The procedure by Samadi5 requires
11 steps from R-(+)-sclareolide (7), while the synthesis
by Bockovich12 was considerably shorter, taking only
three steps from the same starting material. During our
* Corresponding author. Tel.: +34-915622900; fax: +34-915644853.
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01392-8

6352
M. C. de la Torre et al. / Tetrahedron Letters 43 (2002) 6351–6353
described by Bockovich,12 and R-(+)-sclareolide (7) was
submitted to acidic alcoholysis. To our surprise, a
mixture of the three possible unsaturated isomers (8)
was obtained (Eq. (1)). Worse, the mixture was homo-
geneous on all TLC conditions tested, and we were
unable to separate the desired isomer (8b). Because all
the alternative syntheses of aldehyde 5 proceed through
similar mixtures,11 and the synthesis of Samadi was too
long for our purposes, we devised a preparation of
aldehydes 1 and 5 using Weinreb’s amide 9 derived
from R-(+)-sclareolide. Reported herein is a three-step
synthesis of both g-bicyclohomofarnesal 1 and its endo-
isomer 5, from R-(+)-sclareolide (7).
dehydrated in the presence of SOCl2/Py to produce a
mixture of D8(17)- and D7-derivatives (10 and 11, respec-
tively). No D8 isomer was formed in these reaction
conditions. The mixture was easily separated by column
chromatography to give 10 and 11 in 60 and 32%
yields, respectively. These two simple transformations
allowed us to access the desired precursors of the target
compounds 1 and 5. In this regard, compound 10 was
reacted with LiAlH4 in anhydrous THF to form
smoothly the desired g-bicyclohomofarnesal 1 in a
respectable 89% yield.15 Analogously, when the endo-
isomer 11 was submitted to LiAlH4 reduction, the
desired compound 5 was obtained in 91% yield16
(Scheme 1).
In conclusion, g-bicyclohomofarnesal 1 and its endo
isomer 5 were prepared in 47 and 26% overall yields
from commercial R-(+)-sclareolide (7), in a three-step
sequence. This procedure is simple and can compete
with the syntheses previously reported for the prepara-
tion of these important compounds, both in overall
yields and in the number of synthetic steps.
(1)
Acknowledgements
R-(+)-Sclareolide (7) was reacted with the dimethylalu-
minum amide derived from N-methoxy-N-methylamine
yielding the desired Weinreb’s amide 9 in 88% yield
(Scheme 1).13,14 The tertiary alcohol of amide 9 was
Financial support by the Spanish Ministerio de Ciencia
y Tecnolog´ıa (Grant No. BQU2001-1283) is gratefully
acknowledged. I. Garc´ıa thanks the MEC (Spain) for a
predoctoral fellowship.
References
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2. Mori, K.; Tamura, H. Liebigs Ann. Chem. 1990, 361.
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Scheme 1.

M. C. de la Torre et al. / Tetrahedron Letters 43 (2002) 6351–6353
6353
12. Cebula, R. E.; Blanchard, J. L.; Boisclair, M. D.; Pal, K.;
Bockovich, N. J. Biorg. Med. Chem. Lett. 1997, 7, 2015.
13. (a) de la Torre, M. C.; Maggio, A.; Rodr´ıguez, B. Tetra-
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(32), 234 [M]+ (5), 205 (7), 190 (29), 177 (15), 153 (11),
137 (100), 123 (49), 121 (30), 109 (47), 95 (56), 81 (54), 69
(48), 55 (34), 41 (38). Anal. C, 81.52; H, 10.75; calcd for
C16H26O, C, 81.94; H, 11.18%.
16. Preparation of 13,14,15,16-tetranor-7-labden-12-al (5)
from 11. LiAlH4 (80 mg, 2.1 mmol) was added in por-
tions to a solution of amide 11 (125 mg, 0.42 mmol) in
THF (9 mL) at 0°C under argon. The mixture was stirred
at this temperature for 30 min until the amide was
consumed (TLC analysis). Then, 10 mL of water were
added and the reaction mixture was allowed to reach
room temperature and was vigorously stirred for 1 h. The
reaction mixture was extracted with AcOEt (3×20 mL)
and the combined organic layers were dried and concen-
trated under reduced pressure. The residue was purified
over silica gel using hexanes:CH2Cl2 (17:3) as eluent to
give pure 5 as a colorless oil (91 mg, 91%): [h]2D2 −29.2 (c
0.161, CHCl3); IR (neat) wmax 2924, 2847, 2712, 1725,
14. Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett.
1997, 38, 2685.
15. Preparation of 13,14,15,16-tetranor, 8(17)-labden-12-al (1)
from 10. To a suspension of LiAlH4 (129 mg, 3.4 mmol)
in THF (40 mL), under argon and at 0°C, a solution of
amide 10 (500 mg, 1.7 mmol) in THF (50 mL) was added
drop wise. The mixture was allowed to reach room
temperature and it was stirred overnight. The reaction
mixture was quenched by adding 100 mL of a 10% w/v
KOH solution. The mixture was filtered through Celite®,
the organic phase was removed and the aqueous phase
was extracted with AcOEt (3×80 mL). The combined
organic extracts were dried and concentrated under
reduced pressure. The residue was purified over silica gel,
using hexanes:AcOEt (49:1) as eluent, to give 350 mg
(89%) of pure 1 as a colorless oil: [h]2D2 −22.9 (c 0.097,
CHCl3); IR (neat) wmax 3080, 2929, 2844, 2714, 1725,
1
1457, 1443, 1387, 1365, 1054, 1022 cm−1; H NMR (200
MHz, CDCl3) l 9.83 (1H, t, J=2.2 Hz), 5.45 (1H, br s,
H-7), 2.47 (1H, m), 2.35 (2H, m), 1.50 (1H, dd, J=1.5,
2.9 Hz), 0.87 (3H, s), 0.86 (3H, s), 0.75 (3H, s); 13C NMR
(50.3 MHz, CDCl3) l 203.5 (d, C-12), 132.9 (s, C-8),
123.4 (d, C-7), 49.8 (d, C-9)*, 48.5 (d, C-5)*, 42.3 (t, C-3),
42.0 (t, C-1), 39.5 (t, C-11), 36.0 (s, C-10), 33.1 (q, C-18),
32.9 (s, C-4), 23.6 (t, C-6), 22.5 (q, C-17)*, 21.8 (q,
C-19)*, 18.7 (t, C-2), 14.2 (q, C-20) assignments marked
with an asterisk may be interchanged; EI MS m/z (rel.
int.) 234 [M]+ (7), 205 (4), 190 (12), 175 (8), 149 (7), 137
(7), 124 (57), 109 (100), 95 (27), 81 (27), 69 (24), 55 (18).
Anal. C, 81.65%; H, 10.93%; calcd for C16H26O: C,
81.94%; H, 11.18%.
1
1644, 1459, 1388, 1366, 891 cm−1; H NMR (200 MHz,
CDCl3) l 9.61 (1H, dd J=2.38, 1.47 Hz, CHO), 4.80
(1H, br s, HB-17), 4.37 (1H, br s, HA-17), 2.41 (2H, m,
2H-11), 0.88 (3H, s), 0.80 (3H, s), 0.69 (3H, s); 13C NMR
(50.3 MHz, CDCl3) l 203.5 (d, C-12), 148.4 (s, C-8),
108.0 (t, C-17), 55.2 (d, C-9), 50.9 (d, C-5), 41.9 (t, C-3),
39.7 (t, C-1)*, 39.3 (t, C-7)*, 38.8 (s, C-10), 37.4 (t, C-11),
33.4 (q+s, C-18+C-4), 24.0 (t, C-6), 21.8 (q, C-19), 19.3 (t,
C-2), 14.7 (q, C-20) assignments marked with an asterisk
may be interchanged; EIMS m/z (rel. int.) 235 [M+1]+