Synthesis of Polysantol and related sandalwood-type odorants using magnesium α-bromoketone enolates

Article abstract of DOI:10.1016/j.tetlet.2004.01.142

The syntheses of the commercial sandalwood-type odorant Polysantol and several structurally related compounds are described. The methodology followed is based on a selective and efficient magnesium-mediated aldol reaction of the starting material, α-campholenic aldehyde and different α-bromoketones. Dehydration of the resulting secondary alcohol and reduction of the carbonyl group allowed the completion of the syntheses of the target molecules in 30-56% overall yields.

Full text of DOI:10.1016/j.tetlet.2004.01.142

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2619–2622
Synthesis of Polysantolâ and related sandalwood-type odorants
using magnesium a-bromoketone enolates
*
ꢀ
ꢀ
Juan M. Castro, Pablo J. Linares-Palomino, Sofıa Salido, Joaquın Altarejos,
ꢀ
Manuel Nogueras and Adolfo Sanchez
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Quımica Inorganica y Organica, Facultad de Ciencias Experimentales, Universidad de Jaen, 23071 Jaen, Spain
Received 21 November 2003; revised 21 January 2004; accepted 28 January 2004
Abstract—The syntheses of the commercial sandalwood-type odorant Polysantolâ and several structurally related compounds are
described. The methodology followed is based on a selective and efficient magnesium-mediated aldol reaction of the starting
material, a-campholenic aldehyde and different a-bromoketones. Dehydration of the resulting secondary alcohol and reduction of
the carbonyl group allowed the completion of the syntheses of the target molecules in 30–56% overall yields.
Ó 2004 Elsevier Ltd. All rights reserved.
The East Indian sandalwood oil, obtained by steam
distillation of the heartwood and roots of Santalum
album L., is one of the oldest and most valuable per-
fumery raw materials, and it has been used extensively in
perfumery because of its non-varying composition, fix-
ative properties, and sweet, warm, spicy and tenacious
fragrance.1 Due to a general widespread shortage and a
steep rise in the price of this natural oil, great efforts
have been made during the last decades to develop
cheap synthetic substitutes.2 Among these, two classes
of compounds have been commercially successful: the
terpenyl cyclohexanols and the derivatives of a-cam-
pholenic aldehyde 1.2 Within the latter group, Poly-
santolâ 2 is the most expensive and appreciated by
perfumers and its synthesis has been achieved through
aldol condensation of 1 with ethyl methyl ketone 3,
deconjugative a-methylation of the enone 4 and reduc-
tion of 5 (Scheme 1).3 This straightforward process
seems to have in the first step a certain drawback as
compound 4 is usually accompanied by the other aldol
condensation product resulting from the reaction of 3
through the terminal carbon C-1.
As a continuation of our previous studies on the syn-
thesis of odorants,4 we were interested on this occasion
in the synthesis of Polysantolâ 2 and structurally related
compounds. In order to minimize the presence of the
undesired aldol condensation product mentioned above
we envisaged the direct coupling of a-campholenic
aldehyde 1 with the a-bromoketone 7 (Scheme 2)5 by a
magnesium-mediated aldol-type reaction.6 Introducing
a bromine atom7 at the more substituted carbon of
3-methyl-2-butanone 6 should favour the reaction of
compound 7 with 1 preferentially through carbon C-3.5b
In fact, the reaction of 7 with magnesium in refluxing
diethyl ether to generate the corresponding bromo-
magnesium enolate and subsequent coupling to 1, under
experimental conditions similar to the classical Grignard
O
3
i
iii
ii
O
O
OH
CHO
87%
97%
60%
5
2
4
1
Scheme 1. Synthesis of Polysantolâ 2 from a-campholenic aldehyde 1.3 (i) KOH, MeOH–H2O, )5 °C; H2SO4. (ii) NaOH, hexadecyltrimethyl-
ammonium bromide, toluene; MeCl. (iii) NaBH4, EtOH.
Keywords: Polysantolâ; a-Campholenic aldehyde; a-Bromoketones; Magnesium enolates; Aldol reaction; Sandalwood; Odorants.
* Corresponding author. Tel.: +34-953-002743; fax: +34-953-012141; e-mail: jaltare@ujaen.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.142

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J. M. Castro et al. / Tetrahedron Letters 45 (2004) 2619–2622
O
6
i
60%
Br
ii
iii
iv
O
O
O
2
CHO
70%
80%
95%
OH
7
5
1
8
(S/R 4:1)
Scheme 2. Synthesis of Polysantolâ 2 from 1 using the magnesium enolate of 7.5a (i) Br2, AcOH, CCl4.7a (ii) Mg, Et2O, D. 7b (iii) MsCl, Py, 0 °C; LiBr,
Li2CO3, DMF, 150 °C.8a (iv) NaBH4, MeOH, )10 to 0 °C.
reaction,6;7b gave the b-hydroxyketone 8 in 80% yield
(Scheme 2). In this manner, the isomer of 8, formed by
reacting 1 and 7 through the terminal carbon C-1, was
only detected by GC as a minor by-product (2–4%). This
demonstrates that the aldol-type reaction between 1 and
the magnesium enolate of 7 occurs in a more regio-
selective manner than the direct aldol condensation be-
tween 1 and 3 described in the literature.3 In addition, it
is not necessary now to introduce a methyl group by a
further deconjugative a-methylation step as both methyl
groups are present in the starting ketone 6. However,
this a priori advantage turned out to be troublesome as a
consequence of the difficulties encountered in the dehy-
dration of 8. This compound did not eliminate water
easily to give 5 as readily as the corresponding analogue
of 8 (when 1 and 3 reacted to give 4, Scheme 1). After
using different systems we finally obtained 5 in reason-
able yield (70%) by treating 8 with methanesulfonyl
chloride followed by eliminating the resulting mesylate
with lithium bromide and lithium carbonate in N,N-
dimethylformamide (Scheme 2).8a;9 Finally, ketone 5
was reduced with sodium borohydride to give 2 (95%),5a
which means that the synthesis of Polysantolâ 2 has
efficiently been accomplished from a-campholenic alde-
hyde 1 in 53% overall yield (Scheme 2).
Taking into account that the reaction of 1 with the eno-
late of 7 was conducted in a selective and effective way
we were also interested in extending this methodology to
other a-bromoketones in order to determine the scope of
the reaction and prepare several Polysantolâ structurally
related compounds. Thus, a-bromoketones 9–12 were
reacted with magnesium7b to give the corresponding
bromomagnesium enolates, which were reacted in situ
with a-campholenic aldehyde 1 to afford compounds
17–20 in 54–76% yields (Table 1). According to these
data it was evident that the reaction is convenient in
terms of yield and regioselectivity and needed shorter
reaction times when compared with the direct aldol
reactions between aldehyde 1 and ketones 3, 6 and 13–
15. This magnesium-mediated aldol reaction works
better when the starting ketone has both primary and
tertiary carbon atoms on a positions, as for 13 (Table 1)
and 6 (Scheme 2). It is worth noting that longer reaction
times led to a general decrease in the regioselectivity of
the reaction, possibly due to the existence of an inter-
Table 1. Reaction of a-bromoketones 9–12 with a-campholenic aldehyde 1 in the presence of magnesiuma
Starting materialb
Product
Yield (%)c
76 (8)
Br
Br
O
O
O
O
O
OH
17
9
13
O
54 (18)
OH
18
10
14
O
O
O
O
Br
61 (5)
OH
19
11
15
O
O
Br
75 (70)
OH
20
12
3
a See general procedure.7b
b Compounds 9–12 were prepared from the corresponding ketones 13–15 and 3 following the general procedure.7a
c Percentages after column chromatography. Numbers in bracket refer to yields of 17–20 (deduced from the GC analysis of the crude reactions) in the
direct aldol reactions of ketones 3 and 13–15 with 1.

J. M. Castro et al. / Tetrahedron Letters 45 (2004) 2619–2622
2621
R1= R2=Me, R3=H
R1=Me, R2=Et, R3=H
R1= R2=R3=Me
R2
R2
H
R2
7
Br
R1
9
O
Mg
OMgBr
R3
OMgBr
R3
R1
R1
10
H
R3
11 R1= R3=H, R2=Pri
R1= R3=H, R2=Me
II
I
12
Scheme 3.
R1
R1
R1
i
O
O
OH
ii
R2
R2
R2
OH
R1=Et, R2=Me
R1=Me, R2=Et
94%
95%
17 R1=Et, R2=Me
78%
75%
24 R1=Et, R2=Me
21
22
R1=Me, R2=Et
R1=Me, R2=Et
25
18
R
R
O
R
O
iii
OH
iv
OH
R=Pri
67%
71%
R=Pri
R=Me
R=Pri
R=Me
23
26
27
73%
90%
19
20
4
R=Me
Scheme 4. Synthesis of Polysantolâ analogues following the magnesium-mediated aldol-type approach. (i) MsCl, Py, 0 °C; LiBr, Li2CO3, DMF,
150 °C.8a (ii) NaBH4, MeOH, 0 °C. (iii) p-TsOH, toluene, D.8b (iv) (a) KButO, DMF; AcOH, 0 °C. (b) NaBH4, MeOH, 0 °C.
molecular equilibration of the initially formed enolate I
and its isomer II (Scheme 3), through which undesired
products progressively appeared. Furthermore, this
equilibrium could also be responsible for the lower
regioselectivity observed for bromoketone 10 (Table 1)
as the corresponding trisubstituted enolate II
(R1 ¼ R2 ¼ R3 ¼ Me, Scheme 3) should be comparatively
more stable than the disubstituted enolates II resulting
from bromoketones 7, 9, 11 and 12. Continuing with the
synthesis of Polysantolâ analogues, the b-hydroxy-
ketones 17–20 were dehydrated8 to enones 21–23 and 4,
which were reduced with sodium borohydride (23 and 4
were deconjugated prior to reduction),10 to finally give
the target alcohols 24–27 (Scheme 4).5a These final
compounds revealed interesting olfactory properties. In
addition to the well known commercially available
Ebanolâ 27, compound 24 showed a woody note with
strong sandalwood odour, terpenic and a faint aroma of
burning, compound 25 showed a woody note with a
sweet tonality and leather-spicy aspects, and compound
26 was similar to 24 with a clear cedarwood-like note.
aspects of this synthetically useful reaction. Finally,
because of the potential interest of the alcohols prepared
we are currently working on the characterization of pure
isomers and subsequent sensory analysis in order to
further study the structure–activity relationships.
Acknowledgements
We wish to thank the Ministerio de Ciencia y Tecno-
ꢀ
logıa for financial support (R+D Project PPQ2000-
1665) and the Ministerio de Educacion, Cultura y
ꢀ
Deporte for a fellowship to J.M.C. We also thank
Sensient Fragrances S.A. for sensory evaluation and the
gift of technical-grade a-campholenic aldehyde and
some standards.
References and notes
In conclusion, the magnesium enolates of several a-
bromoketones were employed to achieve selective and
effective aldol reactions on a-campholenic aldehyde,
which opened a modified route to the synthesis of the
sandalwood-type odorant Polysantolâ and closely
related compounds in reasonable yields. To our knowl-
edge this is the first time that bromomagnesium enolates
have been used for synthetic purposes since Fellmann
and Dubois studied the aldol condensation of ethanal
with the magnesium enolate prepared from 2-bromo-
2,5,5-trimethyl-cyclopentanone.6;11 Furthermore, the use
herein of ketones with enolisable hydrogens in both a
substituents allowed us to study the regioselectivity
1. Shankaranarayana, K. H.; Parthasarathi, K. Perfum.
Flavor. 1984, 9, 17–20.
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2. Frater, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998,
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3. Schulte-Elte, K.-H.; Muller, B. L.; Pamingle, H. EP155591
(Priority, 23 March 1984, to Firmenich S.A.) [Chem.
Abstr. 1985, 105, 191435q].
4. (a) Linares-Palomino, P. J.; Salido, S.; Altarejos, J.;
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Sanchez, A. Tetrahedron Lett. 2003, 44, 6651–6655; (b)
Castro, J. M.; Salido, S.; Altarejos, J.; Nogueras, M.;
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Sanchez, A. Tetrahedron 2002, 58, 5941–5949; (c) Altare-
jos, J.; Castro, J. M.; Linares, P.; Salido, S.; Nogueras,
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J. M. Castro et al. / Tetrahedron Letters 45 (2004) 2619–2622
International Symposium on the Chemistry of Natural
Products, Florence, 2002; p 135; (d) Castro, J. M.; Salido,
solution of 1 (10.0 mmol, S/R 4:1) in Et2O (15 mL) was
added dropwise. After refluxing for 10 min the mixture
was poured onto 0.5 M HCl (100 mL) and extracted with
Et2O. The organic layer was washed with saturated aq
NaHCO3 and brine, and dried over anhydrous Na2SO4.
After removing the solvent on a rotary evaporator the
residue was purified by silica gel column chromatography
to yield the corresponding b-hydroxyketone. For com-
pounds 19 and 20, an a-bromoketone/1 ratio of 6:5 and
more concentrated solutions were used in order to achieve
better results.
ꢀ
S.; Altarejos, J.; Nogueras, M.; Sanchez, A. One step
preparation of (+)-norambreinolide from sclareol oxide,
23rd International Symposium on the Chemistry of
Natural Products, Florence, 2002; p 164; (e) Palomino,
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F. M.; Salido, S.; Altarejos, J.; Nogueras, M.; Sanchez, A.
Synthesis of potential fragrance compounds from davanone,
a natural odourless tetrahydrofuran derivative, 23rd Inter-
national Symposium on the Chemistry of Natural Prod-
ucts, Florence, 2002; p 299; (f) Linares, P.; Salido, S.;
ꢀ
Altarejos, J.; Nogueras, M.; Sanchez, A. Chlorosulfonic
8. (a) Dehydration of b-hydroxyketones 8, 17 and 18.
General procedure: To a stirred solution of the b-
hydroxyketone (0.2 mmol) in pyridine (2 mL) was added
MsCl (0.3 mmol) at 0 °C. The mixture was allowed to
warm to room temperature and stirred for 1 h. Then, 2 M
HCl (15 mL) was added and the mixture extracted with
Et2O. The organic layer was washed with 2 M HCl,
saturated aq NaHCO3 and brine, and dried over anhy-
drous Na2SO4. After removing the solvent on a rotary
evaporator the residue was dissolved in dry DMF (15 mL)
and LiBr (1.0 mmol) and Li2CO3 (1.2 mmol) were added.
The stirred mixture was heated to 150 °C for 1 h under
argon. The mixture was cooled and diluted with Et2O, and
the organic layer washed with 2 M HCl, saturated aq
NaHCO3 and brine, and dried over anhydrous Na2SO4.
Evaporation of the solvent on a rotary evaporator yielded
the corresponding enone; (b) Dehydration of b-hydroxy-
ketones 19 and 20. General procedure: To a stirred
solution of the b-hydroxyketone (8.5 mmol) in toluene
(15 mL) was added p-TsOH (0.15 mmol). A Dean–Stark
trap device was fitted and the reaction mixture refluxed for
1 h. Then, the mixture was washed with saturated aq
NaHCO3 and brine, and dried over anhydrous Na2SO4.
Evaporation of the solvent on a rotary evaporator yielded
the corresponding enone.
acid as a cyclization agent for preparing cyclic ether
odorants. In Flavour and Fragrance Chemistry; Lanzotti,
V., Taglialatela-Scafati, O., Eds.; Kluwer Academic:
Dordrecht, 2000; pp 101–107.
5. (a) The starting material 1 used in this work had a specific
rotation of )2.2, which corresponds to an optical purity of
ca. 60% ((S)-1/(R)-1 4:1). This means that all compounds
obtained from 1 in this work are nonracemic mixtures of
stereoisomers on which studies to determine configura-
tions have not been carried out; (b) The direct conven-
tional aldol reaction of a-campholenic aldehyde 1 and
3-methyl-2-butanone 6 was previously carried out yielding
the b-hydroxyketone 8 in 32% yield, along with important
amounts of unreacted starting material and other com-
pounds resulting from the alternative aldol reaction attack
of 6 (C-1) to 1.
6. Fellmann, P.; Dubois, J.-E. Tetrahedron 1978, 34, 1349–
1357, and references cited therein.
7. (a) Bromination of ketones 3, 6 and 13–15. General
procedure: A solution of bromine (12 mmol) in CCl4
(5 mL) was slowly added to a stirred solution of the ketone
(12 mmol) in AcOH (1 mL) at room temperature. After 1–
2 h, Et2O was added and the organic layer washed with
40% aq NaHCO3, saturated aq NaHCO3 and brine, and
dried over anhydrous Na2SO4. After removing the solvent
on a rotary evaporator the residue was purified by reduced
pressure distillation to yield the corresponding a-bromo-
ketone; (b) Reaction of a-bromoketones 7 and 9–12 with
1. General procedure: A solution of the a-bromoketone
(20.0 mmol) in Et2O (15 mL) was added dropwise to a
stirred mixture of Mg (20.5 mmol) and Et2O (6 mL) under
argon. Then, the mixture was refluxed for 30 min and a
9. Bolster, M. G.; Jansen, B. J. M.; de Groot, A. Tetrahedron
2001, 57, 5663–5679.
10. Naipawer, R. E. EP 203528 (Priority, 31 May 1985, to
Givaudan Co.) [Chem. Abstr. 1987, 106, 175828].
11. A report of the use of similarly-derived magnesium
enolates in the regioselective addition to enones is:
Bertrand, J.; Gormchon, L.; Mahoni, P. Tetrahedron
1984, 40, 4127–4140.