Application of the asymmetric Diels-Alder reaction of a 2-substituted chiral maleate to the formal synthesis of (-)-β-santalene

Article abstract of DOI:10.1016/S0957-4166(02)00194-5

The asymmetric Diels-Alder addition of chiral 2-substituted maleates to cyclopentadiene is described and applied to the formal synthesis of (-)-β-santalene.

Full text of DOI:10.1016/S0957-4166(02)00194-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 885–889
Application of the asymmetric Diels–Alder reaction of a
2-substituted chiral maleate to the formal synthesis of
(−)-b-santalene
Nicolas Baldovini and Guy Solladie´*
Laboratoire de Ste´re´ochimie associe´ au CNRS, Universite´ Louis Pasteur, ECPM, 25 Rue Becquerel,
67008 Strasbourg Cedex 2, France
Received 16 April 2002; accepted 19 April 2002
Abstract—The asymmetric Diels–Alder addition of chiral 2-substituted maleates to cyclopentadiene is described and applied to the
formal synthesis of (−)-b-santalene. © 2002 Published by Elsevier Science Ltd.
1. Introduction
addition catalyzed by organoaluminium Lewis acids:
with Et2AlCl, readily available dimenthyl fumarate
adds to cyclopentadiene with a diastereoselectivity of
99%.6
Diels–Alder reactions of cyclopentadiene with
dienophiles is a powerful method for the stereoselective
construction of the bicyclo[2.2.1]heptane framework
encountered in various terpenes and natural products.
Asymmetric synthesis of the santalane sesquiterpenes
have frequently been based on this reaction as a key
step1–4 because the appropriate choice of a chiral
dienophile (often in combination with a Lewis acid)
permits control of the stereochemistry of up to four
stereogenic centers in a single operation.
The use of maleates as dienophiles in Diels–Alder reac-
tions is much less common. Unsymmetrical maleates
were introduced in asymmetric Diels–Alder reactions
through a study7 on the diastereoselectivity of the addi-
tion of maleates 1a–c to cyclopentadiene (Fig. 1).
Diastereomeric excesses of up to 98% were obtained
with tert-butyl-2-phenylcyclohexylmaleate 1a but
unfortunately only moderate stereoselectivity with the
more readily available maleates 1b–c derived from men-
thol or borneol (8 and 13% d.e., respectively). Tanaka
et al.8 reported recently good results in the diastereo-
selective Diels–Alder reaction of maleate 1d derived from
A large number of chiral dienophiles are available for
asymmetric Diels–Alder reactions.5 Acrylates or
methacrylates of enantiomerically pure alcohols or
amines are the most popular and fumarates were
among the first reagents to be used in Diels–Alder
Figure 1.
* Corresponding author. E-mail: solladie@chimie.u-strasbg.fr
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00194-5

886
N. Baldo6ini, G. Solladie´ / Tetrahedron: Asymmetry 13 (2002) 885–889
8,8%-BINOL. The introduction of a chiral sulfoxide
substituent on an unsymmetrical maleate (2-sulfinyl-
maleate) is an alternative way to induce asymmetry but
the endo/exo ratio of the adducts is often lower than
with simple maleates, and depends largely on the tem-
perature and the catalyst employed.9,10
4-methyl-3-pentenylcopper-dimethylsulfide complex to
bulky chiral acetylenedicarboxylate esters such as bis-(−)-
menthyl-, bis-(+)-isomenthyl-, and bis-(+)-neomenthyl
acetylenedicarboxylates 4a, 4b and 4c, respectively. The
desired chiral maleates 2a, 2b and 2c were obtained in
excellent yields (Scheme 1).
To the best of our knowledge, the asymmetric Diels–
Alder reaction of the chiral 2-alkyl substituted maleate
2 with cyclopentadiene has never been reported. In the
course of our studies into the preparation of bicy-
clo[2.2.1]heptane natural products, we found that in the
presence of organoaluminium catalysts, 2-butyl- and
2-(4-methyl-3-pentenyl) dimethyl maleates 3a and 3b
reacted with cyclopentadiene at −78°C to afford the
endo adduct quantitatively. The synthetic potential of
the asymmetric version of this transformation was then
explored, and we propose herein an application to the
enantioselective synthesis of b-santalene.
The Lewis acid-catalyzed Diels–Alder reaction of 2a
with cyclopentadiene was then investigated. The best
results were obtained with 2 equiv. of Et2AlCl or
EtAlCl2 at low temperature. Using the same conditions,
the addition was incomplete using trimethylaluminium
and not effective at all with TiCl4, SnCl4, BF3Et2O and
BCl3. Two diastereomeric adducts 5a and 6a were
obtained in a 69/31 ratio (estimated by 1H NMR).
Experiments carried out at −78, −43 and −30°C showed
that the temperature of the reaction had no significant
influence on this ratio and unfortunately, the use of
dienophiles derived from other readily available chiral
auxiliaries 2b and 2c also led to a mixture of
diastereomers in approximatively the same proportions
(Scheme 2).
2. Results and discussion
Diastereomers 5a and 6a could be separated by column
chromatography, and the major one 5a was thus iso-
lated in 61% yield from 2a. This product then could be
used as an intermediate in the synthesis of enantiomeri-
cally pure b-santalene (Scheme 3).
We could efficiently prepare several 2-substituted
maleates by addition of organocopper–dimethylsulfide
complexes to various acetylenedicarboxylates.11 The
addition of butylcopper- and 4-methyl-3-pentenylcop-
per-dimethylsulfide complexes on dimethyl acetylenedi-
carboxylate proceeded in quantitative yields, but the
choice of the alkyl halide as starting material for the
generation of the copper reagent proved to be crucial.
For instance, the butylcopper complex prepared from
butylmagnesium iodide and CuBr,Me2S gave poor
results compared to those obtained from butylmagne-
sium bromide. As our goal was to use chiral 2-substi-
tuted maleates, we carried out the addition of the
Reduction of this adduct with lithium aluminium
hydride afforded the dextrorotatory form of diol 7 in
84% yield. As expected, the same treatment applied to
compound 6a led to the antipodal isomer (−)-7. Selec-
tive hydrogenation of the intracyclic double bond of
(+)-7 with nickel-P212 led quantitatively to 8, which was
subsequently treated with mesyl chloride in the presence
COOR
COOR
COOR
+
Cu(Me2S)MgBr2
COOR
2a : R= menthyl
4a : R= menthyl
2b : R= isomenthyl
2c : R= neomenthyl
4b : R= isomenthyl
4c : R= neomenthyl
Scheme 1.
2a
+
EtAlCl2/CHCl2
COOR
COOR
6a
COOR
COOR
5a
R = Menthyl
Scheme 2.

N. Baldo6ini, G. Solladie´ / Tetrahedron: Asymmetry 13 (2002) 885–889
887
i
ii
5a
OH
OH
OR
OR
8 : R = H
7
iv
iii
9 : R = Ms
iv
I
I
11
vi (ref 2)
OR
10 : R = Ms
12 : R = H
v
(-)-β-santalene
Scheme 3. Reagents: (i) LAH, THF; (ii) Ni-P2, H2, EtOH; (iii) MsCl, Et3N, CHCl2; (iv) NaI, HMPA, 122°C; (v) LAH, THF,
reflux; (vi) (a) PCC, CH2Cl2, (b) NH2NH2, KOH ethylene glycol, reflux.
of triethylamine to afford the dimesylate 9. Several
attempts were made to prepare the monomesylate 10 by
classical elimination methods. At best, the use of 10
equiv. of DBU in refluxing toluene for 24 h gave 10 in
39% yield, together with unreacted 9 and the applica-
tion of longer reaction times decreased the yield with
degradation products. However, in an attempt to pre-
pare the diiodide 11 by treatment of 9 with sodium
iodide in HMPA, the monomesylate 10 was obtained as
the sole product in 42% yield after 1 h 45 min at 120°C,
with no detectable amount of di- or monoiodide. This
yield could be improved to 74% with the use of caesium
carbonate. Unfortunately, all our attempts to reduce
this product directly to b-santalene were unsuccessful:
the use of lithium aluminium hydride led not
surprisingly13 to the alcohol 12 by hydride attack on the
sulfur atom and even lithium triethylborohydride in
toluene gave unwanted results. The reduction of 10 to
12 was indeed optimized to 94%. A 70% overall yield
was finally obtained from dimesylate 9. In a previous
work2 this alcohol had been already transformed to
(−)-b-santalene (the natural enantiomer) in a two-step
procedure: PCC oxidation to the aldehyde and Wolff–
Kishner reduction in 72% overall yield. We were
pleased to find that the specific rotation value of our
product was in perfect agreement with the reported
data.2 The method described herein thus allows the
preparation of (−)-b-santalene starting from readily
accessible compounds.
chiral 2-substituted symmetrical maleate. This reaction
shows moderate diastereoselectivity but uses a very
inexpensive chiral auxiliary and separation of the minor
diastereomer is easy. The described procedure allowed
the preparation of the (−)-b-santalene precursor 12 in
96% e.e.
4. Experimental
4.1. General
According to the literature procedure, 5-bromo-2-
methyl-2-pentene14 was obtained from cyclopropyl-
methylketone in 67% yield and bis-(−)-menthyl
acetylenedicarboxylate 4a could be prepared in four
steps and 66% overall yield15 from the commercially
available and inexpensive acetylene dicarboxylic
monopotassium salt. This last method was also applied
to the preparation of diisomenthyl- and dineomenthyl
acetylenedicarboxylates 4b and 4c.
1H and 13C NMR spectra were recorded on a Bruker
AC-200 spectrometer at 200 and 50 MHz, respectively.
Chemical shifts were in ppm relative to solvent signal
(residual proton signal for proton spectra or carbon
signal for carbon spectra). IR spectra: Perkin–Elmer
257 spectrophotometer in cm−1. Optical rotations:
Perkin–Elmer 241 MC polarimeter between 20 and
25°C. Analytical TLC: precoated Merck silica gel 60F-
254 glass plates; detection by UV (=254 or 365 nm)
and/or visualization by spray reagents (ethanolic
vanillin/H2SO4, p-anisaldehyde/H2SO4 or phospho-
molybdic acid) or iodine. Preparative (column) chro-
matography: silica gel Geduran Si 60 (40–63 m; 70–230
mesh) from E. Merck. Work-up: organic solutions were
3. Conclusion
In conclusion, we have developed a new procedure for
formal synthesis of enantiomerically pure (−)-b-santal-
ene, based on the asymmetric Diels–Alder addition of a

888
N. Baldo6ini, G. Solladie´ / Tetrahedron: Asymmetry 13 (2002) 885–889
dried
using
magnesium
sulfate
monohydrate
a suspension of LiAlH4 (1.0 g, 26.3 mmol) in diethyl
ether (50 mL) and stirred overnight. The mixture was
then quenched with water and filtered. After evapora-
tion, the crude mixture of 7 and menthol was sepa-
rated by column chromatography to give pure
compound 7 as a colorless oil (1.16 g, 84%). [h]2D5 +21
(c 1.12, CHCl3); IR (CHCl3) 3306, 2866, 1460, 1039,
734 cm−1; 1H NMR (CDCl3) l: 6.07 (2H, bs), 5.16
(1H, bt, J=6.72 Hz), 3.3–3.7 (4H, m), 2.79 (2H, bs),
2.69 (1H, bs), 2.65 (1H, bs), 1.85–2.15 (3H, m), 1.69
(3H, s), 1.64 (3H, s), 1.14–1.6 (5H, m); 13C NMR
(CDCl3) l: 17.71, 23.22, 25.72, 38.80, 46.35, 47.23,
49.10, 49.81, 53.46, 63.77, 64.35, 124.99, 131.50,
134.61, 136.27.
(MgSO4·H2O), filtered and concentrated by rotary
evaporation at water aspirator pressure.
4.2. Bis-(−)-menthyl 2-(4-methyl-3-pentenyl)maleate 2a
To a suspension of CuBr(Me2S) (11.8 g, 57.4 mmol) in
anhydrous THF (350 mL) was added dropwise at
−78°C, a solution of Grignard reagent (55.08 g, 1.0
mmol/g) prepared from 5-bromo-2-methyl-2-pentene.
The mixture was stirred during 40 min at −78°C and a
solution of 4a (16.4 g, 42 mmol) in THF (90 mL) was
added slowly and stirred for 4 h at the same tempera-
ture. The mixture was then treated with 400 mL of a
saturated aqueous NH4Cl solution. After decantation,
the aqueous phase was extracted and the resulting
green oil was chromatographed on silica gel to give 2a
as a colorless solid (19.4 g, 97%). [h]2D5 −94 (c 1.19,
4.5. (1S,2S,3R)-2,3-Bis(hydroxymethyl)-2-(4-methyl-3-
pentenyl)bicyclo[2.2.1]heptane (+)-8
CHCl3); IR (CHCl3) 1718, 1726, 2930, 2953 cm−1; H
1
NMR (CDCl3) l: 5.74 (1H, t, J=1.5 Hz), 5.09 (1H,
bt, J=7 Hz), 4.6–4.9 (2H, m), 1.69 (3H, s), 1.60 (3H,
s), 0.82–2.4 (22H, m), 0.92 (3H, d, J=6 Hz), 0.89 (9H,
d, J=6 Hz), 0.80 (3H, d, J=6.7 Hz), 0.75 (3H, d,
J=7 Hz); 13C NMR (CDCl3) l: 16.03, 16.40, 17.71,
20.85, 20.97, 22.08, 23.20, 23.48, 25.69, 25.84, 25.89,
26.14, 31.45, 31.47, 34.36, 34.74, 40.38, 40.90, 47.10,
74.46, 75.34, 119.53, 122.35, 133.18, 150.13, 164.40,
168.46.
To a solution of (+)-7 (0.884 g, 3.75 mmol), and
Ni(OAc)2 (0.14 g, 0.8 mmol) in 95% ethanol (25 mL)
was added in one portion a solution of NaBH4 (22.4
mg, 0.59 mmol) and NaOH (1.5 mg, 0.03 mmol) in
aqueous ethanol (12 mL). The reaction flask was
purged with hydrogen and stirred at room temperature
for 1.5 h. The reaction mixture was then poured into
1N HCl and the mixture extracted with diethyl ether.
The organic phases were washed with brine, dried
(MgSO4) and evaporated to afford 8 as a colorless oil
which crystallized upon standing (0.873 g, 98%). [h]D25
4.3. Bis-(−)-menthyl (1S,2S,3R)-2-(4-methyl-3-pentenyl)-
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate 5a
1
+26 (c 1.18, CHCl3); IR (CHCl3) 3294, 2953 cm−1; H
NMR (CDCl3) l: 5.14 (1H, bt, J=7 Hz), 3.5–4.0 (4H,
m), 2.17 (2H, bs), 1.9–2.1 (2H, m), 1.69 (3H, s), 1.63
(3H, s), 1.1–1.6 (11H, m); 13C NMR (CDCl3) l: 17.68,
21.68, 23.11, 23.55, 25.70, 37.59, 39.07, 40.79, 43.94,
44.77, 53.23, 61.98, 62.80, 125.07, 131.35. Anal. calcd
for C15H26O2: C, 75.58; H, 10.99. Found: C, 75.35; H,
11.35%.
To
a solution of 2a (2.31 g, 4.87 mmol) in
dichloromethane (60 mL) was added at −78°C a solu-
tion 1 M of diethylaluminium chloride in toluene (10
mL, 2 equiv.) followed after 15 min by cyclopentadi-
ene (7 mL, 86 mmol). The resulting mixture was then
stored at −30°C during 14 h and poured into a mix-
ture of 1N HCl and ice. The cloudy solution was
extracted with ether, the organic phases were washed
with water, NaHCO3 solution and brine, and then
dried with MgSO4. After evaporation of the solvent,
the crude mixture of 5a and 6a was chromatographed
on silica gel to afford pure diasteromer 5a (1.60 g,
61%). [h]2D5 −114 (c 1.15, CHCl3); IR (CHCl3) 1736,
4.6. (1S,2S,3R)-2-(4-Methyl-3-pentenyl)bicyclo[2.2.1]-
heptane-2,3-bis(methylmethane sulfonate) 9
To a solution of diol 8 (2.5 g, 10.50 mmol) and tri-
ethylamine (3.17 g, 31.3 mmol) in dichloromethane
(130 mL) was added dropwise at 0°C mesyl chloride
(3.688 g, 32.2 mmol). The mixture was then stirred for
2.5 h at room temperature and quenched by pouring
into a mixture of HCl (1N) and ice, and extracted
with diethyl ether. The organic phase was washed with
brine, dried (MgSO4) and evaporated to give a crude
oil which was purified by column chromatography to
afford 9 as a white solid (3.61 g, 87%). [h]2D5 −13 (c
2954, 2869 cm−1; H NMR (CDCl3) l: 6.55 (1H, dd,
1
J=3.0, 5.7 Hz), 5.93 (1H, dd, J=3.0, 5.7 Hz), 5.08
(1H, bt, J=7 Hz), 4.4–4.6 (2H, m), 3.04 (1H, bs), 2.79
(1H, bs), 2.69 (1H, d, J=1 Hz), 1.69 (3H, s), 1.62
(3H, s), 0.70–2.2 (24H, m), 0.70–0.92 (6×3H, 6×d); 13C
NMR (CDCl3) l: 15.87, 17.87, 21.13, 21.28, 22.16,
22.89, 25.18, 25.75, 31.41, 34.43, 40.82, 41.08, 41.67,
46.13, 46.74, 46.96, 47.07, 53.71, 54.71, 60.44, 74.41,
74.45, 124.38, 131.64, 133.14, 138.63, 172.51, 173.03.
Anal. calcd for C35H56O4: C, 77.73; H, 10.44. Found:
C, 77.61; H, 10.58%.
1
2.18, CHCl3); H NMR (CDCl3) l: 5.08 (1H, bt, J=6
Hz), 4.1–4.3 (4H, m), 3.04 (3H, s), 3.02 (3H, s), 2.39
(1H, bs), 2.16 (1H, bs), 1.99 (2H, dt, J=8.5 Hz), 1.69
(3H, s), 1.63 (3H, s), 1.3–1.7 (9H, m); 13C NMR
(CDCl3) l: 17.65, 20.91, 22.14, 24.10, 25.67, 37.07,
37.18, 37.38, 37.68, 39.73, 44.05, 45.14, 48.43, 67.29,
68.49, 123.67, 132.12. Anal. calcd for C17H30O6S2: C,
51.75; H, 7.66; S, 16.25. Found: C, 51.77; H, 7.81; S,
16.43%.
4.4. (1S,2S,3R)-(4-Methyl-3-pentenyl)-2,3-bis(hydroxy-
methyl)bicyclo[2.2.1]hept-5-ene (+)-7
A solution of 5a (3.15 g, 5.83 mmol) in diethyl ether
(10 mL) was added dropwise at room temperature to

N. Baldo6ini, G. Solladie´ / Tetrahedron: Asymmetry 13 (2002) 885–889
889
4.7. (1S,2S)-3-Methylidene-2-(4-methyl-3-pentenyl)-
bicyclo[2.2.1]heptane-2-methyl methanesulfonate 10
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Compound 9 (47.7 mg, 0.12 mmol) was dissolved in dry
HMPA (1.5 mL) with sodium iodide (187 mg, 1.25 mmol)
and caesium carbonate (50 mg, 0.26 mmol). The mixture
was heated in an oil bath at 122°C for 1.25 h, poured into
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was obtained as a colorless oil (26.6 mg, 74%). [h]2D5 −64
(c 1.35, CHCl3); 1H NMR (CDCl3) l: 5.08 (1H, bt, J=7
Hz), 4.90 (1H, s), 4.57 (1H, s), (2H, AB, JAB=9.5 Hz,
wA=4.21, wB=4), 3.02 (3H, s), 2.71 (1H, bd), 2.28 (1H,
bs), 1.9–2.16 (2H, m), 1.68 (3H, s), 1.61 (3H, s), 1.2–1.8
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C16H26O3S: C, 64.39; H, 8.78; S, 10.74. Found: C, 64.38;
H, 8.90; S, 10.88%.
4.8. (1S,2S)-3-Methylidene-2-(4-methyl-3-pentenyl)-
bicyclo[2.2.1]heptane-2-methanol 12
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was added lithium aluminium hydride (75 mg, 2 mmol).
The mixture was heated under reflux for 30 min and
quenched at 0°C with water, filtered, evaporated and
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We thank the Collectivite´ Territoriale de Corse (CTC) for
financial support in the form of a fellowship.