Enzyme-mediated preparation of enantioenriched forms of trans- and cis-p-menthan-1,8-dien-5-ol

Article abstract of DOI:10.1016/j.tetasy.2006.02.012

The synthesis of the trans-p-menthan-5-ol (±)-1 was carried out by Diels-Alder cycloaddition of 3-keto-1-butenyl-acetate 3 with isoprene followed by Wittig methylenation. PS lipase resolution of the alcohol afforded acetate (-)-5 with 98% ee, which was hy

Full text of DOI:10.1016/j.tetasy.2006.02.012

Tetrahedron: Asymmetry 17 (2006) 792–796
Enzyme-mediated preparation of enantioenriched forms of
trans- and cis-p-menthan-1,8-dien-5-ol
Elisabetta Brenna, Claudio Fuganti, Francesco G. Gatti,*
Marco Perego and Stefano Serra
Dipartimento di Chimica dei Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico, CNR- Istituto di Chimica del
Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy
Received 9 January 2006; accepted 13 February 2006
Available online 24 March 2006
Abstract—The synthesis of the trans-p-menthan-5-ol ( )-1 was carried out by Diels–Alder cycloaddition of 3-keto-1-butenyl-acetate
3 with isoprene followed by Wittig methylenation. PS lipase resolution of the alcohol afforded acetate (ꢀ)-5 with 98% ee, which was
hydrolysed to give (ꢀ)-1. Alternatively, enzymatic hydrolysis of a keto ester followed by Wittig methylenation and hydrolysis affor-
ded the same alcohol with an ee of 86%. The cis-p-menthan-5-ol (ꢀ)-2 was obtained by Swern oxidation of (ꢀ)-1, followed by dia-
stereoselective reduction with L-Selectride without lost of enantiomeric excess.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
these monoterpenes reported in the literature. Builarm
et al. described a synthetic route consisting of a three
step sequence starting from trans-verbenol leading to
the trans-p-mentha-1,8-dien-5-ol (4S,5R)-1 in an overall
yield of 30% with a discrete ee = 78%, whereas, the cis-
isomer (4S,5S)-2 was obtained with an identical ee by
oxidation of the trans-alcohol to the corresponding
ketone followed by diastereoselective reduction to give
the cis-alcohol.4
Recently, we have described a new preparation of
several monoterpenic alcohols in their enantiomerically
enriched forms. Our synthetic approach consisted of
the enzyme-catalysed resolution of racemic p-menthane
alcohols leading to the access of each enantiomer with
good to excellent ee.1 In continuation of this previous
work, we herein report the selective synthesis of the
trans- and cis-p-mentha-1,8-dien-5-ols, that is, (4S,5R)-
1 and (4S,5S)-2 (Fig. 1).2
2. Results and discussion
7
1
The preparation of ( )-1 is outlined in Scheme 1. Our
strategy is based on the Diels–Alder cycloaddition of
the easily available dienophile 3-keto-1-butenyl-acetate,5
that is, 3 (E/Z, 9:1), to the isoprene to give the trans-keto
ester ( )-4. This reaction, which was tested using differ-
ent Lewis6a acids and temperatures, always gave a com-
plex mixture, mainly composed of polymeric side-
products and ( )-4 with excellent diastereoselectivity.
After optimisation studies, which are summarised in
Table 1, the best results were obtained using BF3ÆEt2O
at ꢀ40 ꢁC. Attempts to carry out the thermal cycloaddi-
tion gave ( )-4 in a modest yield.6b The expected trans-
relative configuration of 4 was unambiguously con-
firmed by analysis of the NMR coupling constants of
protons H–C(6) and H–C(1). Indeed, the presence of
two large (J ꢁ 9 and 10 Hz) and just one small
6
2
3
5
OH
OH
4
9
10
8
(4
S,5
R
)-1
(4S,5S )-2
Figure 1. trans- and cis-p-menthan-1,8-5-ol with the p-menthane
numbering.
In spite of its natural occurrence3 and relatively simple
structure, there has been only one selective synthesis of
*
Corresponding author. Tel.: +39 02 23993072; fax: +39 02
23993080; e-mail: Francesco.Gatti@polimi.it
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.02.012

E. Brenna et al. / Tetrahedron: Asymmetry 17 (2006) 792–796
793
Table 1. Cycloaddition of 3 with isoprene in CH2Cl2
Finally, the cis-p-mentha-1,8-dien-5-ol (1S,5S)-2 was
obtained following the same synthetic approach adopted
by Builarm. Thus, Swern oxidation of alcohol (4S,5R)-
1, followed by reduction of the ketone (S)-7 with
L-Selectride8 gave (4S,5S)-2 {[a]D = ꢀ5.4, vs lit.4 [a]D =
ꢀ4.1} in an overall yield of 33%, without any loss of
enantiomeric purity (Scheme 1).
Entry Catalyst Temperature (ꢁC) Time Ratioc Yield (%)
1
2
3
4
5
6
BF3
BF3
SnCl4
ZnCl2
LiClO4
ꢀ78
ꢀ30
rt
rt
rt
16 h 99:1
8 h 99:2
8 h 94:6
3 d 94:6
10 d 95:5
2 d 82:18
28a
43a
16b
10b
3b
45
10b
a Yield of isolated product after crystallisation.
b Yield determined by GC–MS.
c Ratio of diastereoisomers determined by GC–MS.
3. Conclusion
We have succeeded in the preparation of (4S,5R)-1 and
(4S,5S)-2 by simplifying the synthesis and improving
significantly the ee of the previous reported synthesis.
The PS-lipase catalysed acetylation gave better ee com-
pared to the enzyme hydrolysis of its precursor. Finally,
it should be noted that these kinds of synthons might be
the precursors for an alternative synthesis of several nat-
ural products, such as all the D8-tetrahydro-cannabinol
or cannabidiol derivatives.9,10
(J ꢁ 6 Hz) coupling constants for both protons is typical
of a diaxial conformation.
Since, the keto-ester eliminates easily under either basic
or acid conditions, the reaction was quenched with a 7.2
pH phosphate buffer. The purification was carried out
by simple filtration on a pad of silica gel, followed by
crystallisation in hexane to give pure ( )-4.
4. Experimental
Finally, Wittig methylenation of ( )-4, followed by
hydrolysis in MeOH with K2CO3 gave alcohol ( )-1
in an overall yield of 70%.
4.1. General methods
All solvents and reagents were purchased by the suppli-
ers and used without further purification. Burkholderia
cepacia lipase (Lipase PS, Amano Pharmaceuticals
Co., Japan) was employed in this work. GC/MS analy-
ses were performed on an HP 6890 gas-chromatograph
equipped with a 5973 mass-detector, using a HP-5MS
column (30 m · 0.25 mm · 0.25 mm). The following
temperature program was employed: 60 ꢁC (1 min)/
6 ꢁC/min/150 ꢁC (1 min)/12 ꢁC/min/280 ꢁC (5 min).
Chiral GC: DANI-HT-86.19 gas chromatograph; enan-
tiomer excess determined on a Chirasil DEX-CB column
(25 m · 0.25 mm; Chromopack) with the following tem-
perature program: 50 ꢁC (3 min)–0.5 ꢁC/min–70–20 ꢁC/
Since, in our previous investigation on enzymatic resolu-
tion of monoterpenic alcohols, PS lipase proved to be
the best enzyme, either in terms of efficiency or in terms
of enantioselectivity, the resolution of ( )-1 was carried
out under similar conditions using TBME as a solvent
and vinyl acetate, as an acyl donor.1 Thus, after 2 weeks,
corresponding to a conversion of 42% (detected by GC),
the acetate (4S,5R)-5 (ee 98%, by chiral GC) and the
residual alcohol (4R,5S)-1 {[a]D = +43.1, ee = 81%, by
chiral GC of the corresponding acetate (4R,5S)-5} were
separated by column chromatography. Hydrolysis of
(R,S)-5 with K2CO3 in MeOH gave (4S,5R)-1 {[a]D
=
1
ꢀ53.0, vs lit.4 ([a]D = ꢀ41, ee = 78%}.
min–180 ꢁC. H NMR spectra were recorded in CDCl3
solutions, on Bruker spectrometers; DMX (400 1H
MHz). The chemical shift scale was based on internal
TMS. J values are in hertz. Optical rotations were mea-
sured on a Dr. Kernchen Propol digital automatic polar-
imeter. TLC analyses were performed on Merck
Kieselgel 60 F254 plates.
Alternatively, a second strategy was based on the enzy-
matic hydrolysis of the racemic keto-ester. Thus, a solu-
tion of ( )-4 in a mixture of a THF/7.2 pH phosphate
buffer (9:1) was subjected to enzymatic hydrolysis catal-
ysed by PS lipase. After 3 days, corresponding to a con-
version of 48%, the remaining acetate (1S,6S)-4 was
separated from the hydrolysed alcohol (1R,6R)-6.7 It is
noteworthy, that after the separation, the keto-alcohol
resulted in a solid, whereas, any attempt of recrystallis-
ing the resolved keto-ester failed, this is likely due to a
low enantiomeric imbalance. Indeed, the corresponding
acetate (4S,5R)-5, which was obtained by acetylation of
(1R,6R)-6 in pyridine with Ac2O followed by Wittig
methylenation, shown a good ee of 86%, whereas, the
acetate (4R,5S)-5 obtained by methylenation of the
remaining acetate (1S,6S)-4 showed a modest ee of 70%.
4.2. Synthesis of ( )-trans-p-menthan-1,8-dien-5-ol ( )-1
4.2.1. (1RS,6RS)-6-Acetyl-3-methylacetate-cyclohex-3-
enyl ( )-4. To a solution of 3 (40 g, 0.31 mol) in dry
CH2Cl2 (200 mL) and isoprene at ꢀ40 ꢁC was added
dropwise BF3ÆEt2O (86 mL, 0.68 mol) under nitrogen.
After the addition was complete, the stirring was contin-
ued until the complete conversion of 3, usually after 8–
10 h. The reaction mixture was then quenched with a
phosphate buffer (7.2 pH) and extracted with Et2O
(2 · 0.4 L). The organic solvent was removed under re-
duced vacuum and the crude mixture decanted in meth-
anol in order to remove the polymeric by-products.
After evaporation of MeOH the crude was purified on
a silica gel pad and crystallised in hexane at ꢀ20 ꢁC to
obtain pure ( )-4 as a white spongy solid, which was
The resolution of racemic alcohol ( )-6 was not possi-
ble, since any attempt at removing the acetate group,
either by hydrolysis (NaOH, K2CO3), or by transesteri-
fication with MeONa in MeOH always gave partial
elimination or isomerisation.

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E. Brenna et al. / Tetrahedron: Asymmetry 17 (2006) 792–796
p-Menthan Numbering
IUPAC Numbering
1
3
4
5
6
5
2
1
2
OAc
ii
i
3
OR
OAc
6
4
O
O
( )-4
3
iii
R=H, ( )-1
R=Ac,( )-5
iv
( )-1
+
OH
OR
(4R,5S)-1
R=Ac, (4S,5R)-5
v
iii
R=Ac, (4R,5S)-5
R=H, (4S,5R)-1
vi
( )-4
OAc
OR
+
X
X
X=O, (1S,6S)-4
X=O, R=H, (1R,6R)-6
ii
ii
X=CH2, (4R,5S)-5
X=O, R=Ac, (1R,6R)-4
v
X=CH2, R=Ac, (4S,5R)-5
viii
vii
(4S,5R) -1
O
OH
(4S,5S)-2
(S)-7
Scheme 1. Reagents and conditions: (i) 1 equiv BF3ÆEt2O, ꢀ40 ꢁC, isoprene/CH2Cl2 (1:2); (ii) PhH3P@CH2, THF; 0 ꢁC; (iii) K2CO3, MeOH; (iv) PS
Lipase, vinyl acetate, t-butylmethylether; (v) Ac2O pyridine; (vi) PS-lipase, phosphate buffer/THF; (vii) DMSO, (COCl)2, CH2Cl2, ꢀ60 ꢁC, NEt3,
ꢀ60 ꢁC to rt; (viii) L-Selectride, THF.
washed with cold hexane (26.1 g, 43%); 1H NMR,
d = 5.31, (m, 1H, H–C(4)), 5.18 (ddd, J = 10.0, 8.5,
5.8 Hz, 1H, H–C(1)), 2.85 (dt, J = 10, 5.9 Hz, 1H, H–
C(6)), 2.47 (dd, J = 17.2, 5.8 Hz, 1H, H0–C(2), 2.10–
2.25 (m, 6H, H00–C(2)+H–C(5)+Me), 2.01 (s, 3H, Me),
1.65 (s, 3H, Me–C(3)); 13C NMR, d = 209.1, 170.0,
131.5, 118.3, 70.8, 50.9, 35.1, 29.0, 27.0, 22.7, 20.9;
GC/MS: tR = 14.71 min; m/z: 136 (M+ꢀ60, 20),
121(40), 93(100).
(ice-bath cooling). The liquid phase was evaporated
and the residue was purified by column chromatography
using hexane/AcOEt (9:1) affording ( )-5 as a colorless
1
liquid (15.1 g, 78%). H NMR, d = 5.34, (m, 1H, H–
C(2)), 5.05 (ddd, J = 11.0, 8.9, 5.9 Hz, 1H, H–C(5)),
4.75 (m, 2H, CH2–C(8)), 2.32–2.45 (m, 2H, H–C(6),
2.10–2.15 (m, 2H, H–C(4)+H–C(H3)), 1.96–2.08 (m,
4H, H–C(3)+AcO), 1.65–1.72 (m, 6H, C(8)–Me+C(1)–
Me); 13C NMR, d = 171.2, 146.2, 120.63, 112.7, 72.0,
46.8, 36.6, 32.2, 30.8, 23.5, 20.1; GC/MS: tR =
12.55 min; m/z: 134 (M+ꢀ60, 70), 119(100).
4.2.2. ( )-trans-p-Menthan-1,8-dien-5-acetate ( )-5. To
an ice cooled and well stirred suspension of (Ph3PMe)I
(52 g, 0.13 mol) in THF (300 mL) was added dropwise
BuLi (13 mL, 10 M). After 30 min was added a solution
of ( )-4 (19.6 g, 0.1 mol) in THF (40 mL). After 3 h the
reaction mixture was quenched in cool water (200 mL).
The quenched mixture was extracted with Et2O
(2 · 200 mL), and the combined organic phase was
washed successively with satd NH4Cl and with brine,
dried over Na2SO4 and concentrated at reduced pres-
sure. The residue was dissolved in hexane/Et2O 3:1,
and the triphenyloxide eliminated by crystallisation
4.2.3. ( )-trans-p-Menthan-1,8-dien-5-ol ( )-1. To a
suspension of K2CO3 (21.3 g, 154.6 mmol) in MeOH
(150 mL) was added ( )-5 (15.0 g, 77.3 mmol) and after
2 h, the mixture was concentrated under reduced pres-
sure. The residue was then dissolved in Et2O (50 mL)
and washed with brine (2 · 100 mL), the organic phase
was dried over Na2SO4 and concentrated under reduced
pressure. The residue was distilled to give pure ( )-1 as a
1
colourless liquid (11.8 g, 90%). H NMR, d = 5.34, (m,
1H, H–C(2)), 4.96 (m, 1H, H0–C(10)), 4.90 (s, 1H, H00–

E. Brenna et al. / Tetrahedron: Asymmetry 17 (2006) 792–796
795
C(10)), 3.80 (dt, J = 9.6, 5.8 Hz, 1H, H–C(5)), 2.35 (dd,
J = 16.3, 5.3 Hz, 1H, H0–C(6))), 2.19–1.95 (m, 4H, H0–
C(4)+H00–C(6)+H–C(3)), 1.75 (s, 3H, Me), 1.68 (s, 3H,
Me); 13C NMR, d = 146.0, 131.8, 119.8, 113.3, 68.2,
50.0, 38.7, 30.2, 23.0, 19.3; GC/MS: tR = 9.60 min;
m/z: 152 (M+, 5), 137(90), 84(100).
19.5 mmol). After 3 h the reaction mixture was concen-
trated at reduced pressure, and the residue purified by
column chromatography using hexane/AcOEt (9:1) fol-
lowed by bulb-to-bulb distillation afforded (1R,6R)-4
(3.4 g, 90%) as colourless oil; [a]D = ꢀ131.8 (c 1.0,
CHCl3).
4.3. Lipase resolutions
4.4.2. (4R,5S)-trans-p-Menthan-1,8-dien-5-acetate (4R,
5S)-5 and (4S,5R)-trans-p-menthan-1,8-dien-5-acetate
(4S,5R)-5. A sample of both enantiomers of 4, ob-
tained from enzymatic hydrolysis of 4, was methyl-
enated following the same procedure adopted above.
4.3.1. Enzymatic acetylation of ( )-trans-p-menthan-1,8-
dien-5-ol ( )-1: (4R,5S)-trans-p-menthan-1,8-dien-5-ol
(4R,5S)-1 and (4R,5S)-trans-p-menthan-1,8-dien-5-ace-
tate (4S,5R)-5. A mixture of ( )-1 (10.0 g, 65.7 mmol),
PS lipase (7 g), vinyl acetate (5 mL) and tBuOMe
(70 mL) was stirred at rt until the formation of the ace-
tate (monitored by GC) reached a conversion of around
43% (2 weeks). The reaction was stopped by filtration of
enzyme and evaporation of the solvent at reduced pres-
sure. Column chromatography of the residue in gradient
of eluent (hexane/AcOEt , 95:5–80:20) afforded in order:
the acetate (4S,5R)-5 (5.2 g, 41%); [a]D = ꢀ29.3 (c 1.1,
CHCl3); ee 98%, by chiral GC, tR = 36.4 min; and the
alcohol (4R,5S)-1 (5.2 g, 52%), [a]D = +43.1 (c 0.9,
CHCl3. Hydrolysis of (4S,5R)-5 (5.2 g, 26.8 mmol) using
the above described procedure gave pure (4S,5R)-1
Selected data of (4R,5S)-5: [a]D = +21.1 (c 1.0, CHCl3);
ee = 70% by chiral GC.
Selected data of (4S,5R)-5: [a]D = ꢀ25.3 (c 1.1, CHCl3);
ee = 86% by chiral GC.
4.5. Synthesis of (4S,5S)-cis-p-menthan-1,8-dien-5-ol
(4S,5S)-2
4.5.1. (S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-enone
(S)-7. To a solution of (COCl)2 (2.2 g, 17.2 mmol) in
CH2Cl2 (40 mL) under a nitrogen atmosphere and at
ꢀ60 ꢁC was added DMSO (2.0 g, 26.4 mmol). After
10 min was added quickly a solution of (4S,5R)-1
(2.0 g, 13.2 mmol) in CH2Cl2 (10 mL). After 30 min,
the reaction was treated with NEt3 (8.0 g, 79.9 mmol),
and left to reach the rt. Then, the reaction mixture
was quenched with H2O (20 mL) and washed with brine
(2 · 30 mL). The organic phase was dried over Na2SO4
and concentrated at reduced pressure. Purification of
the residue by column chromatography using hexane/
EtOAc gave the ketone (S)-7 (1.4 g, 54%); [a]D =
ꢀ127.2 (c 1.2, CHCl3), lit. [a]D = ꢀ97. 1H NMR,
d = 5.62, (1H, m, H–C(4)), 4.96 (s, 1H, H0-C(9)), 4.83
(s, 1H, H00-C(9)), 3.18 (t, J = 7.8 Hz, 1H, H–C(6)),
2.40–2.89 (m, 2H+2H, H–C(2)+H–C(5)), 1.76 (s, 3H,
Me), 1.71 (br q, 3H, Me); 13C NMR, d = 208.9, 142.7,
132.1, 20.2, 113.0, 55.0, 44.7, 30.2, 22.6, 21.3; GC/MS:
tR = 8.45 min; m/z: 150 (M+, 50), 135(20), 94(100).
(3.9 g, 95%); [a]D = ꢀ53.0 (c 1.0, CHCl3), lit. [a]D
=
ꢀ41. Acetylation of alcohol (4R,5S)-1 (5.2 g, 34.2
mmol) in pyridine (10 mL) with Ac2O (5 mL) gave, after
usual work-up and bulb–bulb distillation, (4R,5S)-5
(5.6 g, 85%); [a]D = +24.1 (c 1.3, CHCl3), ee 81%, by
chiral GC: tR = 38.4 min.
4.3.2. Enzymatic hydrolysis of (1RS,6RS)-6-acetyl-3-
methylacetate-cyclohex-3-enyl ( )-4: (1S,6S)-6-acetyl-3-
methylacetate-cyclohex-3-enyl (1S,6S)-4 and 1-((1R,6R)-
6-hydroxy-4-methyl-cyclohex-3-enyl)ethanone (1R,6R)-
6. A mixture of ( )-4 (10 g, 51 mmol), phosphate buf-
fer (7.2 pH)/THF (200 mL, 9:1), and PS lipase (4 g) was
stirred at rt until the formation of alcohol reached a con-
version around 50% (3 days). Then, the reaction was
stopped by filtration through a pad of Celite, and the
liquid was extracted with Et2O (2 · 100 mL), the com-
bined organic phases were washed with brine
(100 mL), dried over Na2SO4 and concentrated at re-
duced pressure. Column chromatography of the residue
in gradient of eluent (hexane/AcOEt, 95:5–80:20) affor-
ded in order: the keto-ester (1S,6S)-4 (4.4 g, 45%) as a
pale yellow oil; [a]D = +107.3 (c 0.9, CHCl3); and the
alcohol (1R,6R)-6 (3.3 g, 42%) as white solid; [a]D =
ꢀ158.4 (c 1.0, CHCl3); 1H NMR, d = 5.33, (m, 1H,
H–C(4)), 4.11 (br q, 1H, H–C(1)), 2.80 (s, 1H, OH),
2.62 (ddd, J = 10, 5.9 Hz, 1H, H–C(6)), 2.42 (m, 1H,
H0–C(2)), 2.42 (dd, J = 17.2, 5.8 Hz, 1H, H00–C(2)),
2.21 (s, 3H, Me–CO), 1.90–2.12 (m, 2H, H–C(5), 1.69
(s, 3H, Me–C(3));13C NMR, d = 212.4, 132.6, 118.2,
67.9, 54.2, 37.8, 29.1, 27.9, 22.9; GC/MS: tR=11.26 min;
m/z: 154(M+, 30), 136(50), 121(40), 93(100).
4.5.2.
(4S,5S)-cis-p-Menthan-1,8-dien-5-ol
(4S,5S)-
2. To a solution of (S)-7 (1.0 g, 6.7 mmol) in THF
(20 mL), under a nitrogen atmosphere and at 0 ꢁC,
was added a 1 M solution of lithium tri-sec-butylboro-
hydride (10 mL, 10 mmol). After complete reduction
of the ketone the reaction mixture was quenched with
a saturated solution of NH4Cl (10 mL) and washed with
Et2O (3 · 20 mL). The combined organic phase was
washed with a solution of HCl (0.1 M, 2 · 10 mL), with
a saturated solution of Na2CO3 (1 · 10 mL) and finally
with brine (1 · 10 mL). The organic phase was dried
over Na2SO4 and concentrated at reduced pressure.
Purification of the residue by column chromatography
using hexane/EtOAc (8:2) gave the alcohol (4S,5S)-2
(0.6 g, 62%); [a]D = ꢀ5.4 (c 1.0, CHCl3), lit. [a]D =
ꢀ5.3. 1H NMR, d = 5.45, (m, 1H, H–C(2)), 4.92 (s,
1H, H0–C(10)), 4.82 (s, 1H, H00–C(10)), 4.10 (m, 1H,
H–C(5)), 1.95–2.3 (m, 5H, H–C(3)+H–C(4)+H–C(6)),
1.79 (s, 3H, Me), 1.65 (s, 3H, Me); 13C NMR,
d = 146.4, 130.0, 120.1, 110.8, 66.1, 44.2, 38.2, 24.1,
4.4. Determination of ee of each enantiomer of 5
4.4.1. (1R,6R)-6-Acetyl-3-methylacetate-cyclohex-3-enyl
(1R,6R)-4. To a solution of Ac2O (5 mL) in pyridine/
CH2Cl2 (15 mL, 2:1) was added (1R,6R)-6 (3.0 g,

796
E. Brenna et al. / Tetrahedron: Asymmetry 17 (2006) 792–796
23.4, 22.7; GC/MS: tR = 9.60 min; m/z: 152 (M+, 5),
137(90), 84(100).
`
4. Buillar, M.; Balme, G.; Gore, J. Synthesis 1988, 972–
975.
5. Lyle, F. R. U.S. Patent 5,973,257, 1985; Chem. Abstr.
1985, 65, 2870.
6. For Lewis acid or thermal Diels–Alder, see: (a) Reyes, A.;
Acknowledgements
Aguilar, R.; Munoz, A. H.; Zwick, J.-C.; Rubio, M.;
˜
Escobar, J.-L.; Soriano, M.; Toscano, R.; Tamariz, J.
J. Org. Chem. 1990, 55, 1024–1034; (b) Baldwin, S. W.;
Tomesch, J. C. J. Org. Chem. 1974, 39, 2382–2385.
7. The absolute configurations were assigned by transform-
ing the resolved keto-ester into the corresponding terpene
acetate and then comparing the [a]D.
We thanks for the financial support from COFIN-
MURST.
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2. For clarity, we make reference to the p-menthane num-
bering rule only for the final products 1 and 2 and the
acetate derivate 5.
10. For a recent synthesis of D8-THC derivatives starting from
D2-carene, see: Krishnamurtthy, M.; Ferreira, A. M.;
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