Enantioselective synthesis of cis-7-methoxy-calamenene via Claisen rearrangement of an enzymatically resolved allyl alcohol

Article abstract of DOI:10.1016/j.tetasy.2003.11.021

An enantioselective synthesis of cis-7-methoxy-calamenene 1 has been accomplished through the following key-steps: (i) enzymatic resolution of the racemic allyl alcohol 3 to furnish the (R)-enantiomer (ee>99%); (ii) Claisen-orthoester rearrangement of 4 t

Full text of DOI:10.1016/j.tetasy.2003.11.021

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 335–340
Enantioselective synthesis of cis-7-methoxy-calamenene via Claisen
rearrangement of an enzymatically resolved allyl alcohol
Elisabetta Brenna, Claudia Dei Negri, Claudio Fuganti, Francesco G. Gatti*
and Stefano Serra
Dipartimento di Chimica dei Materiali ed Ingegneria Chimica, ÔG. NattaÕ del Politecnico,
Centro CNR per la Chimica delle sostanze Naturali, Via Mancinelli 7, 20131 Milano, Italy
Received 7 October 2003; accepted 12 November 2003
Abstract—An enantioselective synthesis of cis-7-methoxy-calamenene 1 has been accomplished through the following key-steps: (i)
enzymatic resolution of the racemic allyl alcohol 3 to furnish the (R)-enantiomer (ee >99%); (ii) Claisen-orthoester rearrangement of
4 to introduce the isopropyl unit on the benzylic position (99% ee); (iii) diastereoselective reduction of dihydronaphthalene
derivative 11 to give the cis-isomer 12 (98% de); (iv) regioselective introduction of the formyl group by a Vilsmeier reaction followed
by reduction to give 1.
ꢀ 2003 Elsevier Ltd. All rights reserved.
OAc
OH
1. Introduction
R'
R'
R''
R'
CO2Et
CO2Et
b-c
c
Ar
Ar
Ar
The catalytic enantioselective generation of tertiary or
quaternary benzylic carbons continues to remain one of
the main challenges of modern organic chemistry.1
Successful methodologies have been accomplished by
means of hydrogenation,2 metallobenzene addition,3
benzyl lithium derivatives additions,4 alkylations of
arene rings with carbonyls and electron poor olefins5
and intramolecular Heck reaction.6
R'
OH
a
Ar
R''
R'
Ar
R'=H, R''=H
R'=i-Pr, R''=H
R'=H, R''=Me
Scheme 1. (a) Enzymatic resolution of allylic alcohols; (b) hydrolysis
of acetyl derivative; (c) Claisen rearrangement to give the benzylic
stereocentre.
Recently, Fu and co-workers have reported a new
methodology based on the enantioselective isomerisa-
tion of allylic alcohols catalysed by a rhodium/phos-
phoferrocene complex, however the ees were modest
(<87%).7 Instead, in connection with our continuing
interest in developing new synthetic strategies based on
enzyme-mediated resolutions of simple and cheap
starting materials, we found recently that the combina-
tion of Claisen rearrangement8 with enzymatic asym-
metric esterification of allylic alcohols furnishes an
efficient and simple synthetic tool for the generation of
benzylic stereocentres with excellent ee, always higher
than 98% (Scheme 1).9 Thus, we give here a further
demonstration of the efficacy of our synthetic method-
ology culminating on the first, to our knowledge,
enantioselective total synthesis of (1S,4S)-cis-7-meth-
oxy-calamenene 1.10–12
Me
MeO
1
Two main synthetic routes to this class of terpenoid-like
compounds have been so far developed: one consists of
generating the aromatic ring on a preformed chiral
cyclic precursor by benzoannulation reactions.13
* Corresponding author. Tel.: +39-02-23993072; fax: +39-02-239930-
80; e-mail: francesco.gatti@polimi.it
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.021

336
E. Brenna et al. / Tetrahedron: Asymmetry 15 (2004) 335–340
CO2H
However, these reactions are not always applicable to
complex systems, since either epimerisation of benzylic
stereocentres or complete/partial aromatisation pro-
cesses could occur.14 Moreover, a second limitation
arises from the low availability of commercial chiral
precursors suitable for convenient and direct benzo-
annulation reactions. Alternatively, the second strategy,
which is the one that we adopted for the synthesis of cis-
calamenene, requires aromatic rings that in most of the
cases are commercially available. Typically, a chiral
carbon chain, is constructed on the materials by means
of catalytic asymmetric syntheses, to form the final
substituted tetrahydronaphthalene derivatives.15
a-b
c-e
(R)-3
MeO
MeO
5
6
9
h-j
f
X
OH
O
MeO
MeO
7, X=OH
8, X=Br
g
m-n
k-l
MeO
MeO
MeO
O
10
11
o
12
2. Synthesis of cis-calamene
Scheme 3. Synthesis of 12, reagents and conditions: (a) TEOP, 5 mol %
CH3CH2CO2H, 150–155 ꢁC, 7 h; (b) KOH/H2O, MeOH, reflux, 4 h,
78% in two steps; (c) LiAlH4, THF, 0 ꢁC to reflux, 3 h; (d) TsCl,
pyridine, 5 h; (e) LiAlH4, THF, rt, 3 h, (S)-6 ee 98.9%, 85% in three
steps; (f) O3, CH2Cl2/MeOH (9:1), )78 ꢁC, 1 h, NaBH4; (g) NBS, PPh3,
CH2Cl2, 84% in two steps; (h) sodium dimethyl malonate, THF,
refluxing; (i) KOH/H2O, MeOH, reflux, 4 h; (j) 150–160 ꢁC, 1 h, 88% in
three steps; (k) SOCl2, reflux, 0.5 h; (l) AlCl3, benzene, hexane (1:1),
1 h, 0 ꢁC, 73 % in two steps; (m) MeMgCl, THF, rt, 1 h; (n) cat. TsOH,
toluene, 60 ꢁC, 1 h, 95% in two steps; (o) H2, Pd/C, 12 de 98%, 95%.
After some preliminary optimisation experiments, the
enzyme catalysed asymmetric esterification of the race-
mic allylic alcohols 3, prepared by reduction of ketone 2
with NaBH4,16 gave the best results when carried out in
TBME using PS as the enzyme and vinyl acetate as the
acyl donor. The (R)-acetate derivative 4 (46%, ee >99%
by chiral HPLC, for the absolute configuration vide
infra) was easily separated from the (S)-enantiomer of 3
(ee >99%) by trituration in isopropyl ether, then, the
(R)-alcohol was obtained by hydrolysis of 4 in an overall
yield of 44% (Scheme 2).17;18
chiral GC) in an overall yield of 85%. The halide 8 was
obtained in 84% yield in two steps by reductive ozon-
olysis of 6 at )78 ꢁC followed by bromination of the
alcohol 7 with NBS and PPh3. Thus, the C2 elongation
of the aliphatic chain was achieved by malonic synthesis
in the usual way. The 4-(p-anisyl)-5-methylexanoic acid
9 (ee 98.9% vs lit.7 ee 82%), obtained by decarboxylation
of the hydrolysed malonate derivative, was cyclised to
give the tetralone 10. The best result for cyclisation
reaction of 9 to give 10, was obtained an intramolecular
Friedel–Craft reaction of the acid chloride of 9 at 0 ꢁC
(73%).20 In contrast, the direct closure of the ring by
dehydration, using polyphosphoric acid (PPA), gave
rather low yields.11 Finally, treatment of 10 with
methylmagnesium chloride followed by dehydration
with a catalytic amount of TsOH led to 11 in 95% yield
over two steps.21 Catalytic reduction of the double bond
over Pd/C in a preformed H2 atmosphere gave the cis-
diastereoisomer 12 with respect to the trans in the ratio
99:1.
The synthesis of precursor to 7-methoxy-calamenenes 12
is outlined in Scheme 3. Claisen–Johnson rearrange-
ment19 of allylic alcohol (R)-3 with triethyl orthoprop-
ionate, in the presence of a catalytic amount of propionic
acid, furnished a nonchromatographically separable
mixture of the alkenyl ester derivatives and their vinyl
ether precursor. This mixture was hydrolysed affording
the acids 5 (ratio of the two diastereoisomers 60:40, by
1
inspection of OMe H signals) in 78% yield over two
steps, and some of the starting alcohol 3 which could be
easily separated from the acids by an acid–base extrac-
tion. Then, the acids were processed by means of a
reduction/tosylation/reduction reaction sequence in the
usual way affording the hydrocarbon 6 (ee 98.9% by
OH
O
(S)-3
2
MeO
MeO
MeO
a
+
OH
OAc
b
Concerning compound 11, it could adopt two different
conformations: 11a or 11b (Fig. 1). The highly selective
c
( ) 3
4
MeO
OH
H
MeO
MeO
H4
Me
(R)-3
3α Me
H3β
MeO
H3α
11a
i-Pr
H4
Scheme 2. Synthesis of (R)-3, reagents and conditions: (a) NaBH4,
MeOH, 5 h, 88%; (b) PS, TBME, 24 h, rt, (S)-3 45%, ee ¼ 99.1%, by
chiral HPLC, and 4 46%, ee ¼ 99.5% by chiral HPLC; (c) KOH/H2O,
MeOH, reflux, 4 h, (R)-3 95%, ee ¼ 99.5%, by chiral HPLC.
i-Pr
11b
H3β
Figure 1. Conformations of compound 11.

E. Brenna et al. / Tetrahedron: Asymmetry 15 (2004) 335–340
337
6 ꢁC minꢁ1/150 ꢁC (1 min)/12 ꢁC minꢁ1/280 ꢁC (5 min).
1H NMR spectra were recorded in CDCl3 solutions, on
Bruker spectrometers; AC-250 spectrometer (250 MHz
R
a
MeO
MeO
1
1H), DMX (400 MHz H). The chemical shift scale was
12
13 R=CHO
1 R=Me
based on internal TMS. J values are in Hz. Optical
rotations were measured on a Dr. Kernchen Propol
digital automatic polarimeter. TLC analyses were per-
formed on Merck Kieselgel 60 F254 plates. Microanalysis
were determined on the analyser 1106 CarloErba.
b
Scheme 4. Synthesis of cis-7-methoxy-calamenene 1, reagents and
conditions: (a) P2O3Cl4, DMF, 0 ꢁC to reflux, 24 h, 56%; (b) H2, Pd/C,
MeOH, 3 h, 99%.
4.1. (6)-trans-4-(4-Methoxyphenyl)-but-3-en-2-ol 3
formation of cis-isomer is probably due to the pre-
dominant presence of conformer 11b, in which the axial
position of the isopropyl group should favour the
reduction of the double bond from the less hindered
side.
To a stirred solution of trans-4-(4-methoxyphenyl)-3-
buten-2-one (150 g, 0.85 mol) in methanol (1 L) at 0 ꢁC
was added NaBH4 (35.3 g, 0.93 mol). After 2 h the
reaction mixture was refluxed (30 min). Then, the vol-
ume of reaction mixture was concentrated to 0.3 L,
poured in an ice bath and neutralised with HCl (10%).
The white precipitate was filtered and dissolved in DCM
(0.5 L), washed with HCl (2 · 400 mL, 0.1 M) and brine
(1 · 400 mL), dried over Na2SO4 and concentrated under
reduced pressure to give a white-yellow solid, which was
triturated in isopropylether (300 mL) to afford pure 3 as
white powder (133 g, 88%); mp 79 ꢁC; 1H NMR
(250 MHz, CDCl3) d ¼ 7:35 (m, 2H, ArH), 6.85 (m, 2H,
ArH), 6.53 (d, J ¼ 15:7, 1H, CHAr), 6.14 (dd, J ¼ 15:7
and 6.8, 1H, CH@CH), 4.47 (m, 1H, CHOH), 3.83 (s,
3H, OMe), 1.38 (d, J ¼ 7:0, 3H, Me); 13C NMR
(50 MHz, CDCl3) d ¼ 159:2, 131.4, 129.4, 129.0, 127.6,
114.0, 69.3, 55.0, 23.2; GC/MS: tR ¼ 18:69 min; m=z: 178
(Mþ, 37), 163 (15), 121 (100), 115 (15); Anal. Calcd for
C11H14O2: C, 74.13; H, 7.92. Found: C, 74.17; H, 7.94.
Finally, the formyl group was regioselectively added to
the aromatic ring by a Vilsmeier reaction, using pyro-
phosphoryl chloride in DMF, to give the corresponding
aldehyde, that is, 13,22 which was reduced over Pd/C to
give the (1S,4S)-cis-7-methoxy-calamenene 1 in a 55%
overall yield (Scheme 4). The absolute configuration was
20
D
assigned by comparison of the experimental ½aꢀ ¼
20
)30.3 (c 0.92, CHCl3) with the ½aꢀ ¼ )29 (c 0.20,
D
CHCl3) reported in literature.10
3. Conclusion
The first enantioselective total synthesis of cis-calam-
enene has been achieved by combining the enzymatic
asymmetric esterification of racemic allylic alcohol 3
with the Claisen–Johnson rearrangement. All reaction
steps are very simple and proceed with high yields. The
early stereoselective introduction of the isopropyl group
at the benzylic position proved crucial for the generation
of the next stereocentre, since it favoured the diaste-
reoselective reduction of double bond from the less
sterically hindered face. This synthetic plan could be
used for the synthesis of other related calamenenic
structures.23
4.1.1. Procedure for the lipase-catalysed asymmetric
esterification of (6)-trans-4-(4-methoxyphenyl)-but-3-en-
2-ol. To a stirred solution of compound 3 (130 g,
0.73 mol) in TBME (0.5 L) was added PS (10 g) and
vinyl acetate (100 mL). After 15 h the suspension was
filtered and the PS was recovered as it was and it could
be reused for several resolutions. The organic solution
was concentrated under reduced pressure to obtain a
white cream solid, which was triturated in isopropyl-
ether (2 · 200 mL) affording the (S)-3 enantiomer.
The isopropyl solution was concentrated at low pressure
and the resulting residue was purified on a pad of silica
gel using hexane/ethyl acetate (9:1,v/v) affording in
order:
4. Experimental
All solvents and reagents were purchased from the
suppliers and used without further purification. Burk-
holderia cepacia lipase (Lipase PS, Amano Pharmaceu-
ticals Co., Japan) was employed in this work. Chiral
HPLC analyses of compounds 3 was performed on a
Chiralcel OD column (Daicel, Japan) installed on a
Merck–Hitachi L-6200 apparatus: 0.6 mL/min, UV
detector (254 nm), hexane/isopropanol 95:5. GC–MS
analyses were performed on a HP 6890 gas-chromato-
graph 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)/
(R)-trans-2-Acetoxy-4-(4-methoxyphenyl)-but-3-ene 4 as
low melting point white solid (69.8 g, 46%, 99.5% ee
by HPLC, (S) tR ¼ 7:51 min, (R) tR ¼ 8:49 min),
20
D
½aꢀ ¼ <3; 1H NMR (250 MHz, CDCl3) d ¼ 7:37 (m,
2H, ArH), 6.83 (m, 2H, ArH), 6.47 (d, J ¼ 15:7, 1H,
CHAr), 5.92 (dd, J ¼ 15:7 and 6.8, 1H, CH@CH), 3.79–
3.9 (m, 3H+1H, ArOCH3+CHOAc), 3.36 (s, 3H,
CO2CH3), 1.37 (d, J ¼ 7:0, 3H, Me); 13C NMR
(50 MHz, CDCl3) d ¼ 170:1, 159.3, 131.0, 128.9, 127.6,
127.4, 126.4, 113.8, 71.0, 55.0, 21.2, 20.2; GC/MS:
tR ¼ 20:45 min; m=z: 220 (Mþ, 55), 177 (80), 161 (100),
145 (75); Anal. Calcd for C13H16O3: C, 70.89; H, 7.32.

338
E. Brenna et al. / Tetrahedron: Asymmetry 15 (2004) 335–340
Found: C, 70.57; H, 7.34; and the (S)-trans-4-(4-meth-
oxyphenyl)-but-3-en-2-ol 3 that was recombined with
the other (S)-alcohol (59.8 g, 46%, 99.1% ee by HPLC,
4.4. (R)-trans-1-(1-Isopropyl-but-2-enyl)-4-methoxy-
benzene 6
20
(S) tR ¼ 27:98 min, (R) tR ¼ 25:33 min); ½aꢀ ¼ 8.9 (c 1.1,
To a well stirred solution of 5 (45 g, 0.19 mol) in THF
(250 mL) at 0 ꢁC was added portionwise LAH (8.7 g,
0.23 mol). After 2 h the reaction mixture was refluxed for
30 min. The usual work-up was furnished the alcohol as
colourless oil. To a solution of the alcohol in pyridine
(100 mL) was added TsOCl (39 g, 0.21 mol). After 16 h
was added Et2O (200 mL) and filtered the white solid.
The organic solution was washed with HCl (2 · 200 mL,
1 N), brine (1 · 200 mL) and dried over Na2SO4. The
solvent was removed under reduced pressure to yield the
tosyl derivate. To a solution of tosylate in THF
(300 mL) at 0 ꢁC was added portionwise LAH (8.7 g,
0.23 mol). After 3 h the reaction mixture was refluxed for
2 h. The usual work-up afforded a yellow oil, which was
passed on a pad of silica gel with hexane to afford 6 as a
D
20
D
CHCl3) [lit.24 ½aꢀ ¼ 8.15 and lit.16 ee ¼ 98%].
4.2. (R)-trans-4-(4-Methoxyphenyl)-but-3-en-2-ol 3
To a stirred solution of 4 (59 g, 0.28 mol) in EtOH/H2O
(0.5 L, 1:1) was added dropwise a solution of KOH
(24 g, 0.42 mol) in H2O (100 mL) and refluxed. After 5 h
the reaction mixture was washed with DCM
(2 · 300 mL) and the combined organic layers was
washed with HCl (1 · 200 mL), brine (1 · 200 mL) and
dried over Na2SO4. The solvent was removed under
reduced pressure to afford a solid, which was triturated
in isopropylether to give compound 3 (47 g, 95%).
20
D
½aꢀ ¼ )9.0 (c 1.1, CHCl3).
low melting point white solid (32.9 g, 85%); ee 98.9% by
20
D
chiral GC; ½aꢀ ¼ )61.5 (c 2.19, CHCl3); 1H NMR
(400 MHz, CDCl3) d ¼ 7.05–7.12 (m, 2H, ArH), 6.79–
6.86 (m, 2H, ArH), 5.4–5.6 (m, 2H, CH@CH), 3.81 (s,
3H, OMe), 2.73 (t, J ¼ 8:8, 1H, CHPh), 1.83 (m, 1H,
CH(CH3)2), 1.65 (d, J ¼ 6:6, 3H, @CHCH3), 0.93 (d,
J ¼ 6:6, 3H, CH3CH), 0.74 (d, J ¼ 6:6, 3H, CH3CH):
13C NMR (50 MHz, CDCl3) d ¼ 157:7, 137.2, 134.1,
128.6, 125.1, 113.8, 56.4, 55.1, 33.1, 21.0, 20.7, 17.9; GC/
MS: tR ¼ 12:31 min; m=z: 204 (Mþ, 3), 161 (100), 146
(12), 91 (13). Anal. Calcd for C14H20O: C, 82.30; H,
9.87. Found: C, 82.47; H, 9.94.
4.3. (2RS,3R)-trans-3-(4-Methoxyphenyl)-2-methyl-
haxa-4-enoic acid 5
To a solution of (R)-3 (46 g, 0.26 mol) in triethylortho-
propionate TEOP (0.6 L) placed in a 1 L round bottom
flask equipped with a condenser/distillation head was
added propionic acid (5 mL). The reaction mixture was
heated to 150–155 ꢁC and the ethanol was continuously
collected. During the reaction, propionic acid was
occasionally renewed. After 6–7 h the excess of TEOP
was removed by distillation to yield an orange oil resi-
due. To a solution of the residue in EtOH/H2O (0.5 L,
1:2) was added dropwise a solution of KOH (22 g,
0.39 mol) in H2O (100 mL) and refluxed for 6 h. Most of
TEOP was removed under reduce pressure and the res-
idue was washed with Et2O (2 · 200 mL) and dried over
Na2SO4. The combined organic layers was dried over
Na2SO4 and concentrated to give a yellow residue that
was triturated with isopropylether (2 · 50 mL) to give
the starting alcohol (R)-3 (6 g). The water solution was
neutralised with HCl (1 M) and washed with DCM
(3 · 300 mL), the organic layer was dried over Na2SO4
and the solvent was removed under reduced pressure to
give a yellow oil that was passed on a pad of silica gel
using hexane/ethyl acetate (9:1, v/v) affording compound
5 as bright crystalline solid (47.4 g, 77%). 1H NMR
(400 MHz, CDCl3) d ¼ 10:9 (br s, CO2H), 7.05–7.12 (m,
2H, ArH), 6.79–6.86 (m, 2H, ArH), 5.4–5.6 (m, 2H,
CH@CH), 3.77 (s, 2H, OMe), 3.82 (s, 3H, OMe), 2.82 (t,
J ¼ 8:8, CHPh), (br t, J ¼ 7:2, 0.4H, CHCO2H), 2.63–
2.82 (m, 1H, ArCH), 1.65 (dd, J ¼ 5:5, 1.0, 1.8H,
@CHCH3), 1.60 (dd, J ¼ 5:5, 1.0, 1.2H, @CHCH3),
1.19 (d, J ¼ 6:6, 1.8H, CHCH3), 0.96 (d, J ¼ 6:6, 1.2H,
CHCH3); 13C NMR (50 MHz, CDCl3) d ¼ 179:5, 177.3,
158.2, 157.8, 139.2, 138.3, 135.6, 134.2, 131.7, 130.0,
129.3, 128.7, 127.2, 125.2, 115.1, 114.4, 113.7, 55.2, 45.1,
44.7, 41.1, 40.8, 18.8, 18.0, 14.8, 14.2; GC/MS:
tR ¼ 22:09 min minor diastereoisomer, m=z: 234 (Mþ, 6),
161 (100), 146 (11), 91 (12); tR ¼ 22:23 min main dia-
stereoisomer, m=z: 234 (Mþ, 4), 161 (100), 146 (13), 91
(12). Anal. Calcd for C14H18O3: C, 71.77; H, 7.74.
Found: C, 71.64; H, 7.64.
4.5. (S)-2-(4-Methoxyphenyl)-3-methyl-butan-1-ol 7
Ozonolysis of a solution of 6 (31 g, 0.15 mol) in DCM/
MeOH (300 mL, 7:3) at )78 ꢁC gave, quenching with
NaBH4 (3 g, 0.1 mol), alcohol 7. The reaction mixture
was allowed to warm up at room temperature, then, was
washed with HCl (1 · 200 mL), brine (1 · 200 mL), dried
over Na2SO4. The solvent was removed under reduced
pressure to yield 7 as colourless oil (28 g, 92%).
20
D
½aꢀ ¼ +9.4 (c 1.07, CHCl3); 1H NMR (400 MHz,
CDCl3) d ¼ 7:08 (m, 2H, ArH), 6.75 (m, 2H, ArH), 3.89
(dd, J ¼ 4:8, 10.6, 1H, CHOH), 3.75 (m, 3H+1H,
OMe+CHOH), 2.42 (dt, J ¼ 5:3, 8.8, 1H, CHCH2), 1.86
(m, 1H, CHCH3), 0.98 (d, J ¼ 6:6, 3H, CH3), 0.73 (d,
J ¼ 6:6, 3H, CH3); 13C NMR (50 MHz, CDCl3)
d ¼ 157:4, 135.4, 128.9, 113.1, 66.1, 54.7, 48.1, 35.5,
20.6, 20.1; GC/MS: tR ¼ 19:21 min; m=z: 194 (Mþ, 27),
163 (100), 151 (45), 135 (13). Anal. Calcd for C12H18O2:
C, 74.19; H, 9.34. Found: C, 74.47; H 9.86.
4.6. (S)-1-(1-Bromomethyl-2-methoxy-propyl)-4-
methoxy-benzene 8
To a solution of 7 (27.3 g, 0.14 mol) and PPh3 (36.7 g,
0.14 mol) in DCM (0.5 L) at 0 ꢁC was added portionwise
NBS (25 g, 0.14 mol). After 1 h the reaction mixture was
poured in a ice bath, washed with CH2Cl2 (2 · 300 mL),
dried over Na2SO4 and concentrated at reduced pres-
sure. The residue was passed trough a pad of silica gel
using hexane/ethyl acetate (9:1, v/v) affording compound

E. Brenna et al. / Tetrahedron: Asymmetry 15 (2004) 335–340
339
20
8 as yellow oil (32.7 g, 91%); ½aꢀ ¼ )19.6 (c 1.03,
130.0, 120.9, 109.4, 55.3, 44.0, 35.2, 30.1, 24.2, 21.4,
19.6; GC/MS: tR ¼ 22:69 min; m=z: 218 (Mþ, 17), 175
(100), 147 (20), 131 (5). Anal. Calcd for C14H18O2: C,
77.03; H, 8.31. Found: C, 77.22; H, 8.25.
D
1
CHCl3); H NMR (250 MHz, CDCl3) d ¼ 7:08 (m, 2H,
ArH), 6.80 (m, 2H, ArH), 3.75 (m, 3H+1H,
OMe+CHBr), 3.66 (dd, J ¼ 7:0, 10.6, 1H, CHBr), 2.68
(dt, J ¼ 5:3, 8.8, 1H, CHCH2), 2.05 (m, 1H, CHCH3),
0.98 (d, J ¼ 6:6, 3H, CH3), 0.78 (d, J ¼ 6:6, 3H, CH3);
13C NMR (50 MHz, CDCl3) d ¼ 157:5, 135.5, 130.0,
113.2, 54.8, 48.2, 37.8, 35.6, 20.7, 20.4; GC/MS:
tR ¼ 20:51 min; m=z: 256 (Mþ, 23), 213 (70), 163 (5), 134
(100). Anal. Calcd for C12H17BrO: C, 56.04; H, 6.66.
Found: C, 56.27; H, 6.54.
4.9. (1S)-Isopropyl-6-methoxy-4-methyl-1,2-dihydro-
naphthalene 11
To a solution of 10 (6 g, 28 mmol) in THF (100 mL) at
0 ꢁC, under nitrogen atmosphere, was added a solution
of MeMgCl (19 mL, 3 M hexane). After 1 h, the reaction
was quenched with NH4Cl (100 mL), washed with Et2O
(3 · 100 mL), dried over Na2SO4 and the solvent was
removed at reduced pressure. To a solution of the resi-
due in toluene (100 mL) was added a catalytic amount of
TsOH and the reaction mixture was refluxed for 1 h. The
solvent was evaporated at reduced pressure and the
crude residue was purified with column chromatography
4.7. (S)-4-(4-Methoxyphenyl)-5-methylexanoic acid 9
To a solution of sodium malonate freshly prepared
(26.4 g, 0.2 mol) in DMF (0.4 L) at refluxing temperature
was added dropwise a solution of bromide 8 (26.0 g,
0.1 mol). After 6 h the reaction mixture was poured in an
ice bath and washed with AcOEt (4 · 200 mL), dried
over Na2SO4 and concentrated at reduced pressure. To a
solution of the residue in MeOH/H2O (300 mL, 1:1) was
added dropwise a solution of KOH (11.2 g, 0.2 mol) in
H2O (100 mL) and refluxed. After 10 h the reaction
mixture was poured in a ice bath and neutralised with
HCl (1 M), washed with AcOEt, dried over Na2SO4 and
concentrated at reduced pressure. The residue was
heated at 140 ꢁC for 1 h; then, was passed on a pad of
using hexane/EtOAc (95:5) affording 11 as coulorless
20
D
liquid (5.7 g, 95%). ½aꢀ ¼ )40.5 (c 1.03, CHCl3); 1H
NMR (400 MHz, CDCl3) d ¼ 7:01 (d, J ¼ 8:0, 1H,
ArH), 6.80 (d, J ¼ 2:8, 1H, ArH), 6.68 (dd, J ¼ 2:8, 8.0,
1H, ArH), 5.74 (br s, 1H, CH@), 3.83 (s, 3H, OMe),
2.32–2.40 (m, 3H), 2.11 (2, J ¼ 1:8, 3H, CH3C@), 1.86
(dt, J ¼ 6:6, 7.1, 1H, CHCH3), 0.88 (d, J ¼ 6:6, 3H,
CH3), 0.78 (d, J ¼ 6:6, 3H, CH3); 13C NMR (50 MHz,
CDCl3) d ¼ 157:3, 142.4, 135.3, 132.0, 129.1, 126.1,
113.3, 111.4, 55.1, 43.1, 33.2, 32.0, 25.3, 21.4, 19.7; GC/
MS: tR ¼ 20:52 min; m=z: 216 (Mþ, 10), 199 (5), 173
(100), 158 (50). Anal. Calcd for C15H20O: C, 83.28; H,
9.32. Found: C, 83.12; H, 9.15.
silica gel using hexane/ethyl acetate (75:25, v/v) affording
20
D
the acid 9 as colourless oil (20.6 g, 88%). ½aꢀ ¼)6.5 (c
20
1.98, CHCl3) [lit.7 ½aꢀ ¼ )3.8 (c 3.01, CH2Cl2, ee ¼ 82%
D
on the alcohol derivative, by chiral HPLC)], H NMR
1
(400 MHz, CDCl3) d ¼ 7:03 (m, 2H, ArH), 6.80 (m, 2H,
ArH), 3.79 (s, 3H, OMe), 2.04–2.24 (m, 4H), 1.7–1.91
(m, 2H), 0.98 (d, J ¼ 6:6, 3H, CH3), 0.74 (d, J ¼ 6:6,
3H, CH3); 13C NMR (50 MHz, CDCl3) d ¼ 179:8, 157.5,
135.4, 128.9, 113.1, 54.9, 51.2, 33.2, 32.2, 27.9, 20.8,
20.5; GC/MS: tR ¼ 22:85 min; m=z: 236 (Mþ, 173), 193
(70), 175 (5), 147 (50). Anal. Calcd for C14H20O3: C,
71.16; H, 8.53. Found: C, 71.02; H, 8.54.
4.10. (1S,4S)-1-Isopropyl-6-methoxy-4-methyl-
1,2,3,4-dihydro-naphthalene 12
To a suspension of Pd/C in MeOH (50 mL) under H2
atmosphere was added a solution 11 (3 g, 13.9 mmol) in
MeOH (20 mL). After 7 h the reaction mixture was
worked up in the usual way affording 12 as colourless
liquid (2.97 g, ed 98% by GC and 1H NMR, 95%).
20
4.8. (4S)-Isopropyl-7-methoxy-3,4-dihydro-2H-
naphthalene-1-one 10
½aꢀ ¼ )34.8; bp 110 ꢁC at 0.8 mmHg; (c 2.47, CHCl3);
D
1H NMR (400 MHz, CDCl3) d ¼ 7:11 (d, J ¼ 9:0, 1H,
ArH), 6.68 (m, 3H, ArH), 3.78 (s, 3H, OMe), 2.85 (m,
1H), 2.57 (m, 1H), 2.20 (m, 1H), 1.60–1.83 (m, 4H,
CH2CH2), 1.27 (d, J ¼ 6:6, 3H, CH3), 1.02 (d, J ¼ 6:6,
3H, CH3), 0.77 (d, J ¼ 6:6, 3H, CH3); 13C NMR
(50 MHz, CDCl3) d ¼ 157:2, 144.1, 131.9, 129.0, 113.2,
111.3, 55.0, 43.0, 33.1, 31.0, 28.6, 23.2, 21.3, 19.6, 17.4;
GC/MS: tR ¼ 20:49 min; m=z: 218 (Mþ, 7), 175 (100),
160 (7). Anal. Calcd for C15H22O: C, 82.52; H, 10.16.
Found: C, 82.82; H, 10.05.
To a suspension of AlCl3 (7.1 g, 53 mmol) in hexane/
benzene (100 mL, 1:1) at 0 ꢁC was added dropwise a
solution of the acid chloride of the acid 9 (12 g, 51 mmol)
prepared in the usual way with SOCl2. After 1 h the
reaction mixture was poured in an ice bath and treated
with HCl (1 M, 100 mL), washed with Et2O
(3 · 300 mL). The combined organic layers was washed
with NHCO3 (satd, 2 · 200 mL) and brine (200 mL),
dried over Na2SO4 and the solvent was removed at
reduced pressure. The residue was passed on a pad of
silica gel using hexane/AcOEt affording a yellow solid,
4.11. (5S,8S)-8-Isopropyl-3-methoxy-5-methyl-1,2,3,4-
tetrahydro-naphthalene-2-carbaldehyde 13
which was crystallised in hexane yielding the tetralone
20
10 as bright needles (8.4 g, 73%). ½aꢀ ¼ +67.9 (c 1.08,
D
CHCl3); 1H NMR (250 MHz, CDCl3) d ¼ 7:52 (d,
J ¼ 2:4, 1H, ArH), 7.20 (d, J ¼ 8:4, 1H, ArH), 7.06 (dd,
J ¼ 8:4, 2.2, 1H, ArH), 3.83 (m, 3H, OMe), 2.48–2.87
(m, 3H), 1.9–2.2 (m, 3H), 0.98 (m, 3H+3H, CH3); 13C
NMR (50 MHz, CDCl3) d ¼ 198:5, 158.1, 140.0, 133.1,
Pyrophosphoryl chloride (3.7 g, 14.7 mmol) was added
dropwise to a stirred solution of 12 (2.0 g, 9.2 mmol) in
DMF (1 g, 13.8 mmol) at 0 ꢁC. After 30 min the resulting
syrup was heated at 95–100 ꢁC for 24 h. The cold reac-
tion mixture was quenched with a solution AcONa

340
E. Brenna et al. / Tetrahedron: Asymmetry 15 (2004) 335–340
119, 6496; (c) Pippel, D. J.; Curtis, M. D.; Du, H.; Beak, P.
J. Org. Chem. 1998, 63, 2; (d) Geller, T.; Schmalz, H. G.;
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Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2283; (f) Beak,
P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumana-
van, S. Acc. Chem. Res. 1996, 29, 552; (g) Ruano, J. L. G.;
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Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2000, 29, 4114; (c) Paras, N. A.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 7894.
6. (a) Hirai, G.; Koizumi, Y.; Moharram, S. M.; Oguri, H.;
Hirama, M. Org. Lett. 2002, 4, 1627; (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
7. Tanaka, K.; Qiao, S.; Tobisu, M.; Lo, M. M.-C.; Fu,
G. C. J. Am. Chem. Soc. 2000, 122, 9870.
8. For a book or review article on Claisen rearrangement,
see: (a) Ziegler, F. E. Chem. Rev. 1988, 88, 1423; (b) Wipf,
P. In Comprehensive of Organic Chemistry; Trost, M. B.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 5.
9. For example, see: (a) Brenna, E.; Carraccia, N.; Fuganti,
C.; Fuganti, D.; Grasselli, P. Tetrahedron: Asymmetry
1997, 8, 3801; (b) Brenna, E.; Fuganti, C.; Grasselli, P.;
Serra, S. Eur. J. Org. Chem. 2001, 1349; (c) Brenna, E.;
Fuganti, C.; Gatti, F. G.; Passoni, M.; Serra, S. Tetrahe-
dron: Asymmetry 2003, 14, 2401.
10. The cis-7-methoxy-calamenene has been isolated from a
cell culture of the liverwort: Nabeta, K.; Katayama, K.;
Nakagavara, S.; Katoh, K. Phytochemistry 1993, 32, 117.
11. For a racemic synthesis of 1, see: Alexander, J.; Rao, G. S.
K. Tetrahedron 1971, 27, 645.
12. For a diastereoselective synthesis of 1, see: Uemura, M.;
Isobe, K.; Take, K.; Hayashi, Y. J. Org. Chem. 1983, 48,
3855.
13. For recent examples of benzoannulation reactions applied
for the construction of chiral tetrahydronaphthalene
derivatives, see: (a) Corey, E. J.; Palani, A. Tetrahedron
Lett. 1997, 38, 2397; (b) Haddad, N.; Salman, H.
Tetrahedron Lett. 1997, 38, 6087; (c) Brenna, E.; Fuganti,
C.; Serra, S. Synlett 1998, 365; (d) Kocienski, P. J.;
Pontiroli, A.; Qun, L. J. Chem. Soc., Perkin Trans. 1 2001,
19, 2356.
(1 M, 10 mL) extracted with Et2O (3 · 50 mL), dried over
Na2SO4 and concentrated at reduced pressure. Column
chromatography on silica gel, eluting with hexane/
AcOEt (98:2) gave in order the unreacted 12 and the
aldehyde 13 as white solid, which was recrystallised in
20
hexane as needles (2.0 g, 56%). ½aꢀ ¼ )72 (c 0.9,
D
CHCl3); mp 54–56 ꢁC; 1H NMR (400 MHz, CDCl3)
d ¼ 10:40 (s, 1H, COH), 7.69 (br s, 1H, ArH), 6.72 (s,
1H, ArH), 3.89 (s, 3H, OMe), 2.91 (m, 1H), 2.62 (m,
1H), 2.29 (m, 1H), 1.64–1.87 (m, 4H, CH2CH2), 1.30 (d,
J ¼ 6:6, 3H, CH3), 1.02 (d, J ¼ 6:6, 3H, CH3), 0.75 (d,
J ¼ 6:6, 3H, CH3); 13C NMR (50 MHz, CDCl3)
d ¼ 189:7, 159.5, 152.3, 132.4, 128.2, 122.7, 111.2, 55.5,
42.7, 33.8, 30.8, 28.2, 22.9, 21.1, 19.0, 17.1; GC/MS:
tR ¼ 23:87 min; m=z: 246 (Mþ, 5), 203 (100), 175(10).
Anal. Calcd for C16H22O2: C, 78.01; H, 9.00. Found: C,
78.30; H 9.15.
4.12. (1S,4S)-cis-7-Methoxy-calamenene 1
To a solution of 13 (2 g, 8.1 mmol) in MeOH was added
a catalytic amount of Pd/C and left under hydrogen
atmosphere for 6 h. Then, the reaction mixture was
worked up in the usual way affording 1 as colourless
20
D
liquid, which was distilled (2.0 g, 56%). ½aꢀ ¼ )30.3 (c
20
0.9, CHCl3) [lit.9 ½aꢀ ¼ )29 (c 0.20, CHCl3)]; bp 115 ꢁC,
D
1
0.8 mmHg; H NMR (400 MHz, CDCl3) d ¼ 6:90 (br s,
1H, ArH), 6.58 (s, 1H, ArH), 3.80 (s, 3H, OMe), 2.85
(m, 1H), 2.15–2.25 (m, 1H+3H), 2.29 (m, 1H), 1.64–1.87
(m, 4H, CH2CH2), 1.27 (d, J ¼ 6:6, 3H, CH3), 1.02 (d,
J ¼ 6:6, 3H, CH3), 0.76 (d, J ¼ 6:6, 3H, CH3); 13C
NMR (50 MHz, CDCl3) d ¼ 155:5, 141.2, 131.2, 130.2,
123.6, 109.6, 55.1, 42.9, 33.0, 31.0, 28.8, 23.3, 21.3, 19.5,
17.4, 16.0; GC/MS: tR ¼ 20:49 min; m=z: 228 (Mþ, 20),
175 (100), 160 (10). Anal. Calcd for C16H24O: C, 82.70;
H, 10.41. Found: C, 82.58; H, 10.45.
Acknowledgements
14. Nakashima, K.; Imoto, M.; Sono, M.; Tori, M.; Nagasc-
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Jones, P. G. Tetrahedron 2000, 15, 2259.
The authors thank COFIN-Murst for financial support.
References and notes
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