Process-scale total synthesis of nature-identical (-)-(S,S)-7- hydroxycalamenal in high enantiomeric purity through catalytic enantioselective hydrogenation

Article abstract of DOI:10.1002/hlca.200590139

A process-scale stereoselective synthesis of nature-identical (-)-(S,S)-7-hydroxycalamenal (=(-)-(5S,85)-5,6,7,8-tetrahydro-3-hydroxy-5- methyl-8-(1-methylethyl)naphthalene-2-carbaldehyde; (-)-1α) in 96% enantiomeric excess (ee) with the aid of chiral Ru

Full text of DOI:10.1002/hlca.200590139

1776
Helvetica Chimica Acta Vol. 88 (2005)
Process-Scale Total Synthesis of Nature-Identical (À)-(S,S)-7-
Hydroxycalamenal in High Enantiomeric Purity through Catalytic
Enantioselective Hydrogenation
by Tiziana Benincori*a), Silvana Brunob), Giuseppe Celentanoc), Tullio Pilatid), Alessandro Pontid),
Simona Rizzod), Mara Sadae), and Francesco Sannicolo¡*d)e)
a
¡
) Dipartimento di Scienze Chimiche ed Ambientali dell×Universita dell×Insubria, via Valleggio, 11,
I-22100 Como (e-mail: tiziana.benincori@uninsubria.it)
b) INSTM , via Varchi, 59, I-50132 Firenze
c
¡
) Istituto di Chimica Organica Alessandro Marchesini dell×Universita, via Venezian, 21, I-20133 Milano
d) Istituto di Scienze e Tecnologie Molecolari, Consiglio Nazionale delle Ricerche, via C. Golgi, 19,
I-20133 Milano
e
¡
) Dipartimento di Chimica Organica e Industriale dell×Universita, via Venezian, 21, I-20133 Milano
(phone: ‡39-0250-314-174, fax: ‡39-0250-314-139, e-mail: staclaus@unimi.it)
Dedicated to Professor Rolf Huisgen, the highest example to us of combined scientific creativity and method
A process-scale stereoselective synthesis of nature-identical (À)-(S,S)-7-hydroxycalamenal (ˆ(À)-(5S,8S)-
5,6,7,8-tetrahydro-3-hydroxy-5-methyl-8-(1-methylethyl)naphthalene-2-carbaldehyde; (À)-1a) in 96% enantio-
meric excess (ee) with the aid of chiral Ru complexes has been developed. The key step was the enantioselective
hydrogenation of easily accessible 2-(4-methoxyphenyl)-3-methylbut-2-enoic acid (10) to (‡)-11 in a 86% ee
(Scheme 5 and Table 1). A substantial increase in optical purity (96% ee) was achieved by induced
crystallization of the intermediate (‡)-3,4-dihydro-4-(1-methylethyl)-7-methoxy-2H-naphthalen-1-one ((‡)-3).
Computational conformation analysis carried out on the analog (À)-9 rationalized the high diastereoselectivity
achieved in the catalytic hydrogenation of the CˆC bond.
1. Introduction. 7-Hydroxycalamenal1), which corresponds to (À)-(5S,8S)-5,6,7,8-
tetrahydro-3-hydroxy-5-methyl-8-(1-methylethyl)naphthalene-2-carbaldehyde ((À)-1a),
is a sesquiterpene with a cadinene skeleton, isolated for the first time by extraction
from the heartwood of different types of elm (Ulmus rubra and U. glabra) in 1968 [1].
The production of hydroxycalamenal was found to increase in a narrow zone at the
interface between healthy and diseased trees infected with some species of fungi, and to
have in vitro antifungal activity [2]. Like several other sesquiterpene derivatives, it
could be employed in perfumery for the formulation of new types of fragrances,
provided that a reliable synthetic access were available.
1
)
Trivial name and atom numbering.
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 88 (2005)
1777
The structure of natural hydroxycalamenal ((À)-1a), with its relative cis-config-
uration [3] and absolute configuration [4], was elucidated through chemical correlation
and spectroscopic analysis. As for the syntheses of (À)-1a, there are a large number of
publications claiming successful achievement in terms of efficiency, chemical yield, and
optical purity, but the accurate examination of the experimental details of these reports
raises several doubts on the reliability and applicability of many of them. Thus, we
considered worth summarizing the stereoselective synthetic approaches to (À)-1a on
account of the fact that the aim of the research reported in this paper was to find access
to enantiomerically pure, nature-identical hydroxycalamenal, which would have high
preparative value and might even be transferred to pilot-scale level.
Of the many nonstereoselective or partially stereoselective approaches reported in
the literature [5], the first synthesis of 1a deserves mention, since it involves some
intermediates, like the ester of acid 2, a-tetralone 3, and tetraline 4, which, at different
stereochemical-purity levels, are the key intermediates also in many recent synthetic
approaches (Scheme 1) [6].
Scheme 1
A formal total synthesis of (À)-1a in good enantiomeric purity is based on the
isomerization of the nonchiral allyl alcohol 5 to the aldehyde (‡)-6, promoted by the
Rh complexes of a chiral ferrocenyl phosphine [7], followed by reduction to the
aldehyde (‡)-7. The sequence was stopped at the level of acid (À)-2, obtained in 82%
enantiomeric excess (ee), and the six remaining steps were considered to be −trivial×
(Scheme 2).
This reaction scheme for preparing enantiomerically enriched (À)-2 is original, but
its preparative value is rather modest for several reasons. The chiral ligand and the
starting alcohol 5 are commercially not available. The synthesis of the latter requires
LiAlH4 reduction of an ester that is prepared, in turn, through two technologically
difficult procedures in modest yield (40%) [8]. Furthermore, a substrate/catalyst ratio
of 20 :1(mol-equiv.) employed in the rearrangement of 5 to (‡)-6 is unacceptable for
larger-scale preparations.

1778
Helvetica Chimica Acta Vol. 88 (2005)
Scheme 2
The most-recent work in this field refers to an enantioselective synthesis of (À)-7-
methoxycalamenenal ((À)-1b) as an intermediate in the synthesis of cis-7-methoxy-
calamenene ((À)-1c) [9]. Once more, the approach is based on the synthesis of acid
(À)-2 as the key intermediate, which was obtained in 21% yield from allyl alcohol (À)-
(R)-8 through an original, but ten-step-reaction sequence (Scheme 3). The synthesis is
characterized by a stereocontrolled Claisen Johnson rearrangement of (À)-8, effected
with triethyl orthopropionate (TEOP) [10]. The latter was obtained in 99.5% ee by
kinetic resolution of the racemate (not commercially available, but easy to prepare), by
Scheme 3

Helvetica Chimica Acta Vol. 88 (2005)
1779
means of an enzyme-catalyzed asymmetric esterification, followed by alkaline
hydrolysis and column chromatography of the enantiomerically pure (R)-acetate
(Scheme 3). Given the high number of steps, the use of critical reagents such as O3 and
LiAlH4 (twice), and the extensive use of chromatographic purification procedures, this
approach appears more an academic exercise than a method of true preparative value
for the synthesis of (À)-2.
The conversion of acid (À)-2 to (À)-1b follows the sequence outlined in the first
synthesis of 1a, as summarized in Scheme 1. The Friedel Crafts cyclization of the acid
chloride of (À)-2 to the a-tetralone (‡)-3, followed by reaction of the latter with
MeMgCl afforded an alcohol which was dehydrated to the dihydronaphthalene (À)-9
(Scheme 4). Catalytic hydrogenation of the non-aromatic CˆC bond of 9 proceeded
highly diastereoselectively, affording (À)-(S,S)-4 in high yield. The facial selection was
attributed to a preferred conformation in which the i-Pr group of (À)-9 is in axial
position. Finally, Vilsmeier-type formylation of (À)-(S,S)-4 proceeded regioselectively
in position 5 to afford (À)-(S,S)-7-methoxycalamenal ((À)-1b) in modest yield.
Scheme 4
There are some points of the synthesis described above that deserve further
investigation, in particular the accurate check of the enantiomeric purity of
intermediates and final products, since chiral chromatographic analyses were stopped
before ozonization (see Scheme 3), and specific rotatory power was used as the only
criterion to assess the enantiomeric purity of all the subsequent products.
As mentioned above, our aim was to find a superior synthetic access to (À)-1a.
Thus, the synthesis had to be as short as possible and involve inexpensive and
commercially available starting materials, and safe and environmentally friendly
reactions. Furthermore, we wanted to unequivocally establish the enantiomeric purities
of both the intermediates and the final product via chiral HPLC analysis, which
required that we also had to perform a diastereoselective synthesis of (Æ)-1a for the
chromatographic comparison of enantiomers. Furthermore, we considered it worth-
while to verify the conformation of 9 through reliable computational data in order to

1780
Helvetica Chimica Acta Vol. 88 (2005)
have a scientifically valid, not only intuitive, justification for the remarkable
diastereoselection observed in the catalytic hydrogenation of 9 to 4.
2. Results and Discussion. 2.1. Synthesis. As a key step in the synthesis of (À)-1a,
we chose an enantioselective hydrogenation to introduce the stereogenic center
bearing the i-Pr group, namely the hydrogenation of 2-(4-methoxyphenyl)-3-methyl-
but-2-enoic acid (10) to (‡)-11 (Scheme 5). The double homologation of acid (‡)-11
should then afford (À)-2, from which the route to calamenal (À)-1a had been already
opened (Schemes 1 and 4).
Scheme 5
This strategy was based on two considerations. Acid 10 could be easily prepared in
good yields (81%) by Wittig reaction [11] of commercially available ethyl (4-
methoxyphenyl)glyoxylate and isopropylidene(triphenyl)phosphorane, followed by
alkaline hydrolysis of the product. As a second advantage, we have designed and
synthesized some chiral diphosphine ligands with atropisomeric, biheteroaromatic
backbones that form transition-metal (Ru, Rh, Pd) complexes that can be used as very
active, stereoselective catalysts in many homogeneous reactions. By introducing
electron-rich or electron-poor five-membered aromatic heterocycles as scaffolds for
the phosphorus functions, we had prepared a series of electronically tunable
diphosphines, exhibiting high performances both in the hydrogenation of pro-stereo-
genic CˆC and CˆO bonds [12], where electron-rich ligands are required [13], and in
some CÀC bond-forming reactions [14], where electronically medium-rich mediators
are the ligands of choice. Thus, as candidates for the hydrogenation discussed above, we
selected the electron-rich, industrial diphosphines BITIANP and TetraMe-BITIOP, as
well as UlluPHOS [15], which is currently under development.
The enantioselective hydrogenation of 10 has already been described in the
literature with the Rh complexes of different chiral diphosphines as promoters.
Rh(NBD)BF4 complexes of BINAP and Cy-BINAP afforded acid 11 in 60% and 72%
ee, respectively, when the hydrogenation was carried out in MeOH solution at 50 bar
H2 pressure and a substrate/catalyst molar ratio of 160 :1 [16].

Helvetica Chimica Acta Vol. 88 (2005)
1781
Excellent stereoselectivities (96.7% ee) have been reported, when a similar Rh
complex of the (diaminoalkyl)-ferrocenyl-diphosphine 12 was employed under
analogous experimental conditions in the presence of 5 mol-% of Et3N. A lower
substrate/catalyst ratio of 150 :1, the commercial unavailability of ligand 12, and a
reaction time of 30 h were the drawbacks of this otherwise appealing synthetic method
[17].
The Ru and Rh complexes of TetraMe-BITIOP, BITIANP, and UlluPHOS were
then tested as promoters in the hydrogenation of 10. Complexes 13a,b and 14a,b were
prepared in situ by reaction of the free diphosphines with [Ru(p-cymene)I2]2 and
[Rh(COD)2]BF4 in MeOH or CH2Cl2 solution, respectively. Complex 13c, which is
being produced on an industrial scale, was supplied by the company owner of the patent
[18].
Hydrogenation experiments on 10 (Table 1), and its ethyl ester, have been
performed at temperatures between 0 and 508 under different H2 pressures (3
100 bar), in line with literature reports for the reduction of a,b-unsaturated carboxylic
acids and esters. We found the ethyl ester to be completely unreactive under a great
variety of experimental conditions. Promising results, however, were obtained with acid
10 and Ru catalyst 13c. Here, compound 11 was obtained after 15 h in quantitative
chemical yield, with 86% ee (HPLC), when working at 100 bar H2 pressure at a
temperature of 358, and with a 10/13c ratio of 500 :1( Table 1, Entry 1). Increasing the
substrate/catalyst ratio up to 2000 :1gave rise to longer reaction times, without
affecting stereoselectivity (Entries 2 and 3).
Negative effects both on kinetics and stereoselectivity were observed at lower
pressure (Entry 4) and, surprisingly, at lower temperature (Entry 5). Also, the Ru
complexes 13a,b turned out to be less enantioselective than 13c (Entries 6 and 7). In
addition, the BITIANP complex 13b was kinetically less active than 13a, as expected on
the consideration of the lower electronic availability of the former ligand. Finally, the
two Rh complexes 14a,b exhibited unexpectedly poor activities (Entries 8 and 9).

1782
Helvetica Chimica Acta Vol. 88 (2005)
Table 1. Enantioselective Hydrogenation of 10 to 11 (see Scheme 5)
Entry
Catalyst
10/Catalysta)
Temperature
[8]
H2 Pressure
[psi]
Time
[h]
Conversion
[%]
eeb)
[%]
1
2
3
4
5
6
7
8
9
13c
500 : 1
1000 : 1
2000 : 1
500 : 125
500 : 1
35
25
25
730
0
1470
1470
1470
2040
1470
1470
70
15
20
48
1
48
48
100
100
100
86
86
86
70
100
100
75
83
13a
13b
14a
14b
500 : 1
25
500 : 125
500 : 150
500 : 130
470
1
48
80
40
40
240
243
1
1
a) Molar ratio. b) Enantiomeric excess.
As for the stereochemical outcome of the hydrogenation reaction of 10, we found
that the (À)-(R)-TetraMe-BITIOPÀRu complex 13c produced the (‡)-(S) antipode of
11. Even though 86% ee was somewhat below our expectations, we considered this as
acceptable, at first instance, given the simplicity, the reliability, and the economical
validity of the process. Moreover, as the benzylic H-atom of 11 is quite acidic due to the
a-COOH group, manipulations directed at improving the optical purity were risky, and
we, thus, decided to continue the synthesis, and to increase the enantiomeric purity of a
more-advanced intermediate.
Next, (‡)-11 was quantitatively reduced with BH3 in THF to the corresponding
alcohol (‡)-15 (Scheme 6), with no loss in enantiomeric purity (86% ee by HPLC).
25
D
The specific optical rotatory power of this product, ‰aŠ ˆ ‡9.2 (c ˆ 1.06, CHCl3), was
found to be nearly identical to that reported in the literature for a material claimed as
25
D
−nearly enantiomerically pure× (‰aŠ ˆ ‡9.4 (c ˆ 1.07, CHCl3)) [9]. This observation
further confirmed the validity of our investigation.
Next, we considered alternative approaches to shorten the reaction sequence
described in the literature to convert alcohol (‡)-15 into the carboxylic acid (À)-2a,
involving the conversion into the corresponding halogenated derivative, followed by
nucleophilic substitution of the halogen atom with diethyl malonate, alkaline hydrolysis
of the product, and decarboxylation, as outlined in Scheme 3. We felt it necessary to
change this synthetic sequence because, in our hands, halogen displacement was
accompanied by elimination as an undesired side reaction.
We directly performed the Mitsunobu reaction on alcohol (‡)-15 with ethyl
1
cyanoacetate to give a 2.3 :1mixture ( H-NMR) of two diastereoisomers 16. This
mixture was directly submitted to alkaline hydrolysis with KOH in ethylene glycol at
1108. Decarboxylation of the resulting diastereoisomeric acids was effected in refluxing
xylene in the presence of copper chromite (5 weight-%), followed by filtration of the
crude product on a silica-gel pad to remove tarry materials. By this sequence, (À)-2 was
obtained in 80% overall yield (Scheme 6).
The enantiomeric excess of (À)-2 was still 86% (HPLC), indicating that the whole
sequence proceeded without loss in optical purity. As expected, the Mitsunobu reaction
gave rise to poor yields, when diethyl malonate was used in place of ethyl cyanoacetate
[19]. We did not succeed in substantially improving the optical purity of (À)-2 by

Helvetica Chimica Acta Vol. 88 (2005)
1783
Scheme 6
fractional crystallization of the diastereoisomeric salts with (‡)- or (À)-a-phenylethyl-
amine. We found that well-formed crystals were grown with the dextro-rotatory amine
from solvents such as AcOEt or (i-Pr)2O, but the benefit was too modest in terms of
both ee and yield to consider this route practicable.
Conversion of (À)-2 to nature-identical 7-hydroxycalamenal ((À)-1a) was then
effected via the traditional route described in Scheme 4. However, we decided to
perform the cyclization to (‡)-3 directly with the acid, rather than its chloride, to avoid
equimolar amounts of AlCl3, which is difficult to dispose. The yield of the
polyphosphoric acid (PPA) promoted internal acylation was acceptable (70%). HPLC
analysis showed that the enantiomeric excess (86%) was fully maintained in crude
(‡)-3.
We made the interesting observation that careful crystallization from MeOH
25
D
produced nice crystals of enantiomerically pure (‡)-3 (99.4% ee by HPLC; ‰aŠ ˆ ‡74
(c ˆ 1.0, CHCl3)), even though in low yield. However, when a saturated hexane
solution of (‡)-3 (86% ee) was seeded with crystals of enantiomerically pure (‡)-3,
25
D
crystallization started immediately, and material of 95.5% ee (by HPLC; ‰aŠ ˆ ‡71
(c ˆ 1.0, CHCl3) was formed in good yield, a residue (56% ee) being obtained from the
mother liquors. This fortunate observation was rationalized on the basis of the higher
solubility of the racemate than that of the pure antipodes. This situation is typical for
conglomerates, and was suggested for tetralone 3 on the basis of different, consistent
observations: the trend in melting points of mixtures of different composition of (‡)-
and (À)-3 was typical for conglomerates; the IR spectra of mixtures of different
composition of (‡)- and (À)-3 were found to be identical; X-ray-diffraction analysis of
a crystal of 3 (Fig. 1) selected from a slightly unbalanced mixture (the racemate is an oil
at room temperature) demonstrated that the crystal was chiral and constituted by
homochiral molecules. The latter experiment provided the structure of 3, even though
the absence of atoms with large anomalous scattering did not permit the determination
the absolute configuration.
On the basis of this result, the route to (À)-1a in high enantiomeric purity was open,
since the synthetic procedures from a-tetralone 3 to 7-hydroxycalamenal (1a) are
described in detail in the literature [5][9]. The reaction of (‡)-3 with MeMgBr,

1784
Helvetica Chimica Acta Vol. 88 (2005)
Fig. 1. ORTEPIII Projection of the X-ray crystal structure of 3 at 150 K. Atomic displacement parameters at the
50% probability level; H-Atoms not to scale.
immediately followed by acid-promoted dehydration of the resulting alcohol in
refluxing toluene, gave (À)-9 in 95% overall yield. The latter was immediately2)
submitted to catalytic hydrogenation (5% Pd/C) to afford (À)-4 in 96% ee (HPLC).
The minor (1S,4R)-diastereoisomer, could be removed by chromatography (SiO2;
hexane/AcOEt 95 :5)3). The high diastereoselectivity observed in the hydrogenation of
9 was justified by a computational study (see below). Then, a classic Vilsmeier reaction
was performed on (À)-4 with P2O3Cl4 and DMF in refluxing 1,2-dichloroethane
(Scheme 4). The reaction was slow (20 h), and required continuous addition of P2O3Cl4
to go to completion. Compound (À)-1b was thus obtained in 80% yield (96% ee by
HPLC). Its rapid demethylation to (À)-1a was effected in high yield with BBr3. The
enantiomeric purity of nature-identical (À)-7-hydroxycalamenal was found to be 96%
(HPLC).
2.2. Conformational Analysis. Due to the size of compound 9 (118 electrons),
calculations were performed at the B3LYP/6-31G(d) level on a model system (M9),
where the Me group in 4-position and the MeO group are replaced by a H-atom and an
OH group, respectively. This alleviates the computational burden and has no
foreseeable effect on the conformational analysis. Minimum-energy structures were
located for the two isomers with the i-Pr group in axial (Ma9) or equatorial position
(Me9), and characterized by harmonic analysis. The energy of both isomers was also
calculated as a function of the relative conformation of the i-Pr group with respect
to the −cyclohexadiene× ring, specifically as a function of the dihedral angle
H(20)ÀC(15)ÀC(21)ÀH(22) (Fig. 2). For each dihedral angle, all other geometrical
parameters were optimized with the Gaussian98 suite [20].
2
)
Exposure of 9 to O2 (air) leads to complete aromatization, and the resulting naphthalene by-product is
difficult to remove by conventional techniques.
The progress of the hydrogenation must be carefully followed, since prolonged reaction times give rise to
the formation of diastereoisomeric methoxydecalines as side products, which have to be removed by
chromatography.
3
)

Helvetica Chimica Acta Vol. 88 (2005)
1785
Fig. 2. B3LYP/6-31G(d) Minimum-energy structure of the Ma9 (left) and Me9 (right) isomers
In both isomeric models, Ma9 and Me9, the lowest-energy structure has a strictly
planar arene ring and a distorted −cyclohexadiene× ring. Indeed, the non-aromatic CˆC
bond is not perfectly coplanar with the arene ring. This distortion amounts to 15.6 and
À 14.08 for the axial and equatorial conformer, respectively. As for the relative
conformation of the i-Pr group with respect to the −cyclohexadiene× moiety, the former
assumes a staggered conformation about the C(15)ÀC(21) bond in both isomers. In
Ma9, H(22) of the i-Pr group points toward the ring center (dihedral angle
q[H(20)ÀC(15)ÀC(21)ÀH(22)] ˆ À178.98), whereas in Me9 it roughly points towards
the aromatic H-atom in position 8 (q ˆ À64.08). As expected for a −cyclohexadiene×
system lacking any 1,3 diaxial interactions, Ma9 is more stable than Me9 by
0.79 kcalmolÀ1. This seemingly tiny difference translates into a 79 :21ratio of M 9/
a
Me9 at room temperature. Furthermore, both isomers have two more lowest-energy
structures corresponding to the other possible staggered conformations of the i-Pr
group. In Ma9, these corresponds to conformations where one of the i-Pr Me groups
points toward the center of the −cyclohexadiene× moiety, thus most effectively hindering
one side of the CˆC bond (q ˆ À66.9 and 64.28). In Me9, the two other stable
conformations have dihedral angles of q ˆ À156.8 and 72.48. It is worth noting that the
equatorialÀequatorial interactions between the i-Pr group and the neighboring H-
atoms in positions 2 and 8 give rise to q values significantly different from the nominal
values of 1808 and 608. The relative energies of the six most-stable conformers are
summarized in Table 2.
Applying the Boltzmann distribution, it turns out that 89% of the molecules display
the i-Pr group in axial position, with a preference for the conformer with q ˆ À178.98.
The remaining conformers (11%) exhibit an equatorial i-Pr group, of which only the
conformer with q ˆ À64.08 is appreciably populated. Finally, the energy of both
conformers was calculated for a fixed q value, and by optimizing all other geometric
parameters, thus outlining a potential-energy curve for the rotation about the
C(15)ÀC(21) bond in both isomers (Fig. 3).
The rotation of the i-Pr group with respect to the cyclic moiety can be considered
free, since the rotation barriers were calculated to be lower than ca. 8 kcalmolÀ1. It is

1786
Helvetica Chimica Acta Vol. 88 (2005)
Table 2. Relative Energy (E) andDihedral Angle q (rotation about the C(15)ÀC(21) bond, see Fig. 2) of the
Most-Stable Structures of the Axial andEquatorial Conformers Ma9 and Me9, Respectively. Populations refer to
estimated Boltzmann distributions.
Conformer
q [8]
E [kcal/mol]
Population [%]
two minimaa)
79
six minimab)
continuumc)
Ma9
À 178.9
À 66.9
64.2
À 64.0
À 156.8
72.4
0.00
0.22
0.58
0.7961
2.71
3.24
43
30
16
63
22
9
Me9
211
< 1
< 1
< 0.1
< 0.1
a) Obtained by considering only the most-stable conformers. b) Obtained considering all stable conformers.
c) Obtained by interpolating the calculated energy by a sixth-order Fourier series.
Fig. 3. B3LYP/6-31G(d) Relative Energies (E) of Ma9 (circles) and Me9 (triangles) as a function of the
H(20)ÀC(15)ÀC(21)ÀH(22) dihedral angle q. Near or at q ˆ 08, there is no stable structure with the i-Pr group
in equatorial position. The curves represent energy interpolations by a sixth-order Fourier series.
noteworthy that for conformers with q values equal or close to 08, there is no stable Me9
structure because of steric repulsion between the i-Pr group and the neighboring H-
atoms.
By a Fourier series analysis up to sixth order, the energies of Ma9 and Me9 can be
interpolated over the whole q range and the Boltzmann distribution. Partitioning such
distribution, another estimate of the population of the various isomers is obtained, as
reported in Table 2. In this case, the Ma9 isomer population is 94%, even larger than in
the −six-minima case×. In conclusion, the present conformational analysis based on
B3LYP/6-31G(d) calculations, and on three different population estimates, provides
evidence that the axial isomer is largely predominant over the equatorial one, which

Helvetica Chimica Acta Vol. 88 (2005)
1787
supports the view that the large diastereoselectivity in the catalytic reduction of 9 is
caused by a conformational effect.
3. Conclusions. We have developed a reliable synthesis of both enantiomers of 7-
hydroxycalamenal (1a) in high enantiomeric purities. The 13-step synthesis is the
shortest reported to date, starting from commercially available materials, and lacking
any risky or environment-polluting reagents. Each step was carefully verified with
respect to both reproducibility and enantiomeric purity. Several points left unclear by
previous work on these subjects were re-investigated and clarified. Hence, our synthetic
scheme represents the currently solely efficient and reliable approach to nature-
identical 7-hydroxycalamenal (1a).
We thank Dr. Lara De Benassuti (Dipartimento di Chimica Organica e Industriale, University of Milan) for
NMR analysis, and Chemi S.p.A. (via Vadisi, 5-03010-Patrica, Frosinone, Italy) for the loan of TetraMe-BITIOP.
T. B. thanks the Dipartimento di Chimica Organica e Industriale of the University of Milan for hospitality.
Experimental Part
General. Unless otherwise specified, all solvents and reagents were reagent-grade, and used without
purification. For the preparations of the complexes and for hydrogenation reactions, solvents were degassed
with Ar. Complex 13c was supplied by Chemi S.p.A. (Italy), and complexes 13a,b were prepared according to
literature procedures [11], starting from the appropriate diphosphine ligand and [Ru(p-cymene)I2]2. Complexes
14a,b were prepared by reaction between [Rh(COD)2BF4] and tetraMe-BITIOP or UlluPHOS [15],
respectively, in CH2Cl2 solution at room temperature. All reactions were performed using standard Schlenk
techniques. HPLC Analyses were performed on a Jasco instrument (model 980-PU pump with 975-UV
detector), with a Chiracel OD column at a flow rate of 0.8 ml/min, detection at 254 nm, the mobile phase being
different hexane/i-PrOH mixtures. 1H-NMR spectra were recorded in CDCl3 soln. on 200- or 300-MHz Bruker
spectrometers; d in ppm, J in Hz.
(2S)-2-(4-Methoxyphenyl)-3-methylbutanoic Acid ((‡)-11). General Procedure. Asymmetric hydrogena-
tion reactions were carried out in a stirred (550 rpm), 100-ml Parr Hastelloy autoclave equipped with a sampling
pipe extending to the bottom of the vessel. The autoclave was purged with Ar (5Â). Then, a soln. of 2-(4-
methoxyphenyl)-3-methylbut-2-enoic acid (10) in degassed MeOH (15 ml) and the suitable catalyst were loaded
into the autoclave by means of a syringe. The autoclave was pressurized with H2 at the desired pressure, and the
soln. was stirred for the time indicated in Table 1. When the reaction was complete, the pressure was released,
and the solvent was evaporated under reduced pressure. The residue was dissolved in a hexane/AcOEt 9 :1
mixture, and filtered over a pad of SiO2 to remove the catalyst. The enantiomeric purity of (‡)-11 was
determined by chiral HPLC (hexane/i-PrOH/HCO2H 88 :1 2 :0.1 ).
(2S)-2-(4-Methoxyphenyl)-3-methylbutan-1-ol ((‡)-15). A 1m BH3 soln. in THF (60 ml, 0.06 mol) was
dropped slowly under N2 to a soln. of (‡)-11 (6.5 g, 0.031mol) in anh. THF (30 ml), keeping the temp. at À 58.
The mixture was stirred for 1h at 0 8, then allowed to warm to room temperature, and stirring was maintained for
a further 8 h. A soln. of AcOH (5 ml) and H2O (5 ml) was cautiously added, and the mixture was stirred until gas
evolution stopped. The THF was evaporated in vacuo, and a sat. aq. Na2CO3 soln. was added to the residue.
After 20 min of stirring, CH2Cl2 was added, and the org. layer was separated, dried (Na2SO4), and concentrated
under reduced pressure. The residue was filtered over a pad of SiO2 (hexane/AcOEt 1:1) to afford pure ( ‡)-15
25
D
in 99% yield and 86% ee (chiral HPLC; hexane/i-PrOH/HCO2H 90 :1 0 :0.1 ).‰aŠ ˆ ‡9.2 (c ˆ 1.07, CHCl3).
Ethyl (2RS,4S)-2-Cyano-4-(4-methoxyphenyl)-5-methylhexanoate (16). A 40% toluene soln. of diethyl
azodicarboxylate (DEAD; 14.7 ml, 0.032 mol) was diluted with THF (25 ml), and the resulting mixture was
added to a soln. of Ph3P (8.6 g, 0.032 mol) in anh. THF (25 ml), and cooled to À 208. Then, a soln. of (‡)-15
(5.5 g, 0.028 mol) and ethyl cyanoacetate (3 ml, 0.028 mol) in THF (50 ml) was added. The mixture was stirred
for 3 h at À 208, and then at r.t. for 20 h. The solvent was removed under reduced pressure, and the residue was
subjected to column chromatography (CC) (SiO2; hexane/AcOEt 8 :2). The first fractions eluted gave 16 (92%)
as a mixture of diastereoisomers in a 2.3 :1ratio, as calculated on the basis of the NMR integrals of H ÀC(2) at
d(H) 3.04 (major) and 3.24 (minor). Most of the other signals were superimposed. 1H-NMR (300 MHz,

1788
Helvetica Chimica Acta Vol. 88 (2005)
CDCl3): 0.74, 0.77 (2d, J ˆ 6.7, 1 MeCH of each isomer); 0.99, 1.02 (2d, J ˆ 6.7, 1 MeCH of each isomer); 1.27,
1.29 (2t, J ˆ 7.2, MeCH2 of each isomer); 1.83 (2m (superimposed), HÀC(5)); 2.17, 2.35 (2m (superimposed),
CH2(3)); 2.53 (2m (superimposed), HÀC(4)); 3.04 (dd, J ˆ 12.1, 4.3, HÀC(2) of major isomer); 3.24 (dd, J ˆ
9.6, 3.9, HÀC(2) of minor isomer); 3.82 (2s (superimposed), MeO of both isomers); 4.14, 4.23 (2q, J ˆ 7.2,
MeCH2 of each isomer; 6.87, 7.04 (2d, J ˆ 8.74, 2 arom. H of minor isomer); 6.89, 7.11 (2d, J ˆ 8.66, 2 arom. H of
major isomer).
(S)-4-(4-Methoxyphenyl)-5-methylhexanoic Acid ((À)-2). Compound 16 (6.4 g) was added to a soln. of
KOH (37 g) in ethylene glycol (110 ml), and the mixture was heated at 1108 for 36 h. The solvent was
evaporated in vacuo, the residue was taken up in CH2Cl2 (60 ml), and extracted with H2O (60 ml). The org. layer
was separated, dried (Na2SO4), and evaporated under reduced pressure. The resulting residue was dissolved in
xylene (100 ml), and this mixture was refluxed for 1 h in the presence of reduced copper (0.15 g) as catalyst. The
solvent was evaporated in vacuo to give a residue, which was purified by CC (SiO2; hexane/AcOEt 7:3) to
afford (À)-2 in 85% yield and 86% ee (chiral HPLC; hexane/i-PrOH/HCO2H 95 :5 :0.1). [a]D ˆ À4 (c ˆ 3.01,
CH2Cl2).
(4S*)-3,4-Dihydro-4-(1-methylethyl)-7-methoxy-2H-naphthalen-1-one ((‡)-3). Acid (‡)-2 (3 g) was added
to polyphosphoric acid (PPA; 30 g) preheated at 808. The mixture was stirred for 1h, then poured onto ice
(30 g), and extracted with CH2Cl2 (20 ml). The org. layer was separated, dried, and concentrated in vacuo, and
the resulting residue was filtered over a pad of SiO2 (hexane/AcOEt 7:3) to afford (‡)-3 in 70% yield. An anal.
sample (86% ee) was subjected to chiral HPLC (hexane/i-PrOH 98 :2) to confirm the enantiomeric purity.
Another sample was slowly crystallized from MeOH at 08 to afford crystals of (‡)-3 [m.p. 738 for 99.4% ee;
25
‰aŠ ˆ ‡74 (c ˆ 1.0, CHCl3)]. These crystals were used as seeds for the crystallization of the whole batch of 3
D
25
D
from hexane. The product recovered by filtration (1.5 g) had an ‰aŠ value of ‡ 71( c ˆ 1.0, CHCl3),
corresponding to 95.5% ee.
(1S,4S)-1,2,3,4-Tetrahydro-6-methoxy-4-methyl-1-(1-methylethyl)-naphthalene ((À)-4). The enantiomeric
excess (ee) was determined by chiral HPLC (Chiracel OD; hexane/i-PrOH/HCO2H 95 :5 :0.1).
(1S,4S)-cis-7-Methoxycalamenal (ˆ(À)-(5S,8S)-5,6,7,8-Tetrahydro-3-methoxy-5-methyl-8-(1-methylethyl)-
naphthalene-2-carbaldehyde; (À)-1b). The enantiomeric excess was determined by chiral HPLC (Chiracel
OD; hexane/i-PrOH/HCO2H 99 :1:0.1).
(1S,4S)-cis-7-Hydroxycalamenal (ˆ(À)-(5S,8S)-5,6,7,8-Tetrahydro-3-hydroxy-5-methyl-8-(1-methylethyl)-
naphthalene-2-carbaldehyde; (À)-1a). The enantiomeric excess was determined by chiral HPLC (Chiracel
OD; hexane/i-PrOH/HCO2H 99.8 :0.2 :0.1).
X-Ray Crystallographic Analysis of Compound 34). Crystallized from hexane. Crystallographic data:
formula, C14H18O2; Mr, 218.28; crystal size: 0.37  0.14  0.05 mm; orthorhombic, space group P212121; a ˆ
7.6924(9), b ˆ 8.6127(12), c ˆ 17.796 (3) ä; Vˆ 1179.0(3) ä3; Tˆ 150 K; Z ˆ 4; Bruker SMART-APEX CCD
area-detector diffractometer, MoKa radiation (l ˆ 0.71073 ä); Dx ˆ 1.230 g cmÀ3; m ˆ 0.080 mmÀ1; w and f
scans, qmax ˆ 30.068; 18775 reflections collected, 1989 unique, 1890 with I0 > 2s(I0), Raver ˆ 0.0305. The structure
was solved with SIR2002 [21], and refined by full-matrix least-squares based on F2 using SHELX97 [22].
Anisotropic C- and O-atoms, H-atoms isotropic; 217 parameters, R(F) ˆ 0.0426, wR(F2) ˆ 0.1021, S ˆ 1.158;
final residues on Fourier map in the range À 0.22 to 0.312 e äÀ3. Without atoms with large anomalous scattering,
we could not determine the absolute configuration, which was, thus, assigned arbitrarily; Fig. 1 was generated
with ORTEPIII [23].
REFERENCES
[1] M. Frachebond, J. W. Rowe, R. W. Scott, S. M. Fanega, A. J. Buhl, J. K. Toda, Forest Prod. J. 1968, 18, 37;
B. O. Lindgren, C. M. Svhan, Phytochemistry 1968, 7, 1407.
[2] R. S. Burden, M. S. Kemp, Phytochemistry 1984, 23, 383.
[3] J. Belavadi, S. N. Kulkarni, Ind. J. Chem., Sect. B 1978, 16, 747.
[4] J. W. Rowe, J. K. Toda, Chem. Ind. 1969, 27, 922; J. W. Rowe, M. K. Seikel, D. N. Roy, E. Jorgensen,
Phytochemistry 1972, 11, 2513; K. Nabeta, K. Katayama, S. Nakagawara, K. Katoh, Phytochemistry 1993,
32, 1 1 7.
4
)
The full crystallographic data of 3 were deposited with the Cambridge Crystallographic Data Centre, 1 2
Union Road, Cambridge CB2 1EZ, UK. The data can be obtained, free of charge, via the internet at
www.ccdc.cam.ac.uk/data_request/cif by referring to CCDC-267608.

Helvetica Chimica Acta Vol. 88 (2005)
1789
[5] F. Bohlmann, W. Mailahn, Chem. Ber. 1981, 114, 1091; K. Takaki, M. Okada, M. Yamada, K. Negoro, J. Org.
Chem. 1982, 47, 1200; M. Uemura, K. Isobe, K. Take, Y. Hayashi, J. Org. Chem. 1983, 48, 3855; K. Takaki,
M. Okada, M. Yamada, K. Negoro, J. Chem. Soc., Perkin Trans. 1 1984, 741; M. Uemura, K. Isobe, Y.
Hayashi, Chem. Lett. 1985, 91; J. Tanaka, M. Takashi, N. Iwasaki, K. Adachi, Bull. Chem. Soc. Jpn. 1992,
2851.
[6] J. Alexander, K. G. S. Rao, Tetrahedron 1971, 27, 645.
[7] K. Tanaka, S. Quiao, M. Tobisu, M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 9870.
[8] T. Sakamoto, F. Shiga, A. Yasuhara, D. Uchiyama, Y. Kondo, H., Yamanaka, Synthesis 1992, 746.
[9] E. Brenna, S. Dei Negri, C. Fuganti, F. G. Gatti, S. Serra, Tetrahedron: Asymmetry 2004, 15, 335.
[10] W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Broksom, T.-T. Li, J. Am. Chem. Soc. 1970, 92, 741.
[11] R. Raap, C. G. Chin, R. G. Micetich, Can. J. Chem. 1971, 49, 2143.
¡
[12] T. Benincori, E. Brenna, F. Sannicolo, L. Trimarco, P. Antognazza, E. Cesarotti, F. Demartin, T. Pilati, J.
¡
Org. Chem. 1996, 61, 6244; T. Benincori, E. Cesarotti, O. Piccolo, F. Sannicolo, J. Org. Chem. 2000, 65, 2043;
¡
T. Benincori, S. Rizzo, F. Sannicolo, J. Heterocycl. Chem. 2002, 39, 471.
¡
[13] T. Benincori, O. Piccolo, S. Rizzo, F. Sannicolo, J. Org. Chem. 2000, 65, 8340.
¡
[14] L. F. Tietze, K. Thede, R. Schimpf, F. Sannicolo, Chem. Commun. 1999, 1811; L. F. Tietze, K. Thede, F.
¡
Sannicolo, Chem. Commun. 2000, 583.
¡
¡
[15] T. Benincori, T. Pilati, S. Rizzo, F. Sannicolo, J. Org. Chem., submitted; F. Sannicolo, O. Piccolo, T.
Benincori, M. Sada, A. Verrazzani, S. Tollis, E. Ullucci, L. De Ferra, S. Rizzo, to Chemi S.p.A., Italy, WO
patent 03074169; EP 1490173.
[16] I. Takemoto, N. Kawamura, H. Kaminaka, Biotech. Biochem. 1994, 58, 2071.
[17] T. Hayashi, N. Kawamura, Y. Ito, J. Am. Chem. Soc. 1987, 109, 7876.
¡
[18] P. Antognazza, T. Benincori, E. Brenna, E. Cesarotti, F. Sannicolo, L. Trimarco, to Chemi S.p.A., Italy, US
Patents 5,907,045 (1999); 6,077,958 (2000); 6,133,191 (2000); 6,297,387 B1 (2001); 6,297,387 B1 (2001); and
6,586,357 B1(2003).
[19] O. Mitsunobu, Synthesis 1981, 1 .
[20] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski,
J. J. A. Montgomery, R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin,
M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S.
Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, N. Rega, P. Salvador, J. J.
Dannenberg, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, A. G.
Baboul, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson,
W. Chen, M. W. Wong, J. L. Andres, C. Gonzalez, M. Head-Gordon, E. S. Replogle, J. A. Pople, Gaussian
98, Revision A.11.3, Gaussian, Inc., Pittsburgh, 2002.
[21] M. C. Burla, M. Camalli, B. Carrozzini, G. L. Cascarano, C. Giacovazzo, G. Polidori, R. Spagna, J. Appl.
Crystallogr. 2003, 36, 1103.
[22] G. M. Sheldrick, SHELX97, Program for the Refinement of Crystal Structures, University of Gˆttingen,
Germany, 1997.
[23] M. N. Burnett, C. K. Johnson, Report ORNL-6895, Oak Ridge National Laboratory, Tennessee, USA,
1996.
ReceivedMarch 29, 2005