Biocatalyzed preparation of the optically enriched stereoisomers of 4-methyl-2-phenyl-tetrahydro-2H-pyran (Doremox)

Article abstract of DOI:10.1139/v02-042

The four stereoisomers of the rose oxide analogue Doremox were prepared in enantiomerically enriched form by enantiospecific bakers' yeast reduction of suitable derivatives and by lipase-mediated kinetic resolution of diol precursors.

Full text of DOI:10.1139/v02-042

714
Biocatalyzed preparation of the optically enriched
stereoisomers of 4-methyl-2-phenyl-tetrahydro-
2H-pyran (Doremox®)
Elisabetta Brenna, Claudio Fuganti, Sabrina Ronzani, and Stefano Serra
Abstract: The four stereoisomers of the rose oxide analogue Doremox® were prepared in enantiomerically enriched
form by enantiospecific bakers’ yeast reduction of suitable derivatives and by lipase-mediated kinetic resolution of diol
precursors.
Key words: yeast, lipase, odorant, reduction, kinetic resolution.
Résumé : Faisant appel à une réduction énantiospécifique de dérivés appropriés à l’aide de levure de boulanger ou à
une résolution cinétique de diols précurseurs à l’aide de lipase, on a préparé une forme énantiomériquement enrichie
des quatre stéréoisomères du Doremox®, un analogue de l’oxyde de rose.
Mots clés : levure, lipase, odorant, réduction, résolution cinétique.
[Traduit par la Rédaction] Brenna et al. 723
Introduction
tivity is mainly determined by vapor pressure, which de-
pends in turn on molecular weight. The phenyl group
increases the mass, without a substantial change of the shape
of the molecule, and thus without affecting the main odour
characteristics (8).
The use of cyclic ethers as fragrant ingredients for the
preparation of perfuming compositions and perfumed arti-
cles originated with the two diastereoisomeric rose oxides
(2S,4R)-cis-1 and (2R,4R)-trans-1, after their discovery in
rose oil (1) and geranium oil (2) and their availability
through efficient synthetic procedures (3).
In the aim of improving the olfactory properties of 1, sev-
eral structural modifications were realized. For example, the
isobutenyl unit was elongated to produce sesquiterpenoid
homologues showing a rather complex odour profile (4), or
one carbon atom of the tetrahydropyrane ring was substi-
tuted with an oxygen atom, to afford chiral 3-oxa analogues
(5).
In 1993, 4-methyl-2-phenyl-tetrahydro-2H-pyran (Doremox®, 2)
was obtained by Firmenich (6) as a mixture of the two
racemic cis- and trans-diastereoisomers, by hydrogenation
of 5,6-dihydro-4-methyl-2-phenyl-2H-pyran in the presence
of Pd on charcoal. This preparation represented a further
evolution in the structure–activity study of the olfactory
properties of rose oxide. The isobutenyl fragment of 1 was
substituted with a phenyl group, to increase the substantivity
of rose scent, i.e the persistence of the perfume material on
blotters, skin, or in the intended application (7). Substan-
Received 9 January 2002. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 31 May 2002.
This paper is dedicated to J. Bryan Jones on the occasion of
his 65th birthday in recognition of his contributions to
biocatalysis.
E. Brenna,1 C. Fuganti, S. Ronzani, and S. Serra.
Dipartimento di Chimica, Materiali, ed Ingegneria Chimica
del Politecnico, Centro CNR per lo Studio delle Sostanze
Organiche Naturali, Via Mancinelli 7, I-20131 Milano.
The two isomers (cis-2 and trans-2) were separated by
preparative gas chromatography, and their odour properties
1Corresponding author (e-mail: elisabetta.brenna@polimi.it).
Can. J. Chem. 80: 714–723 (2002)
DOI: 10.1139/V02-042
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Brenna et al.
715
Scheme 1. (i) Diisobutylaluminum hydride in toluene; (ii) MnO2
in hot DMF; (iii) baker’s yeast; (iv) CHCl3, TosCl, pyridine;
(v) MeONa, MeOH.
Scheme 2. (i) Baker’s yeast; (ii) LiAlH4, THF; (iii) CHCl3,
TosCl, pyridine; (iv) MeONa, MeOH.
diastereoselective reduction of 1,5- and 1,4-difunctionalized
synthons. Thus, as for the synthesis of 2, we envisaged
hydroxy aldehyde 3 and keto acid 4 as substrates for yeast
fermentation.
Compound 3 was prepared according to this synthetic
scheme. Reformatsky reaction of bromo derivative 5 (12)
with benzaldehyde afforded a mixture of hydroxy ester 6
and lactone 7 (13) which were easily separated by column
chromatography. DIBAL reduction of compound 6 in tolu-
ene solution gave unsaturated diol (E)-8 (Scheme 1), which
was straightforwardly oxidized to the desired aldehyde (E)-3
(14) with MnO2 in hot DMF; no oxidation of the benzylic
hydroxylic group was observed in this reaction condition.
Keto acid 4 was prepared according to the following
route. Friedel–Crafts acylation of benzene with the mono-
chloride monomethyl ester of 3-methyl glutaric acid (9) (15)
in the presence of aluminum(III) chloride gave mainly keto
ester 10 (16), which was hydrolyzed with potassium hydrox-
ide in methanol to afford keto acid 4 (17). Derivatives (E)-3
and 4 were incubated with BY for 24 h, and, interestingly
enough, the two reactions took different stereochemical
courses.
were described (6). The racemic cis-diastereoisomer was
found to be very powerful and to have a green, rose oxide –
diphenyl oxide type note. The racemic trans-isomer had a
much weaker odour, with a green, vegetable, slightly dirty
and minty character and a floral undertone. Both of them
were described to be useful in the preparation of perfumes
and concentrated perfuming bases, as well as of a variety of
articles, such as soaps, bath or cosmetic formulations, air
and body deodorants, detergents, fabric softeners, and
household products.
Reduction of the double bond of derivative 3 (Scheme 1),
in the presence of the benzylic stereocentre previously cre-
ated without steric control, gave mainly (80%, GC–MS) diol
(1S,3S)-syn-11 (ee > 99%, chiral HPLC) and a minor quan-
tity (20%, GC–MS) of diol (1R,3S)-anti-11 (ee > 99%,
chiral HPLC). The mixture of the two diastereoisomeric
diols was converted into the corresponding monotosylate de-
rivative 12 and, after treatment with sodium methylate in
methanol, a sample of Doremox® with the following compo-
sition was obtained: (2S,4S)-trans-2, 86%, ee = 99% (chiral
GC); (2R,4S)-cis-2, 14%, ee > 99%, [ ]2D0 + 18.1 (c = 0.75,
CHCl3).
Neither enantioselective synthesis of the four stereoiso-
mers of Doremox®, nor olfactory evaluation of each distinct
isomer have been performed so far. The wide diffusion of
this fragrant component in many commercial preparations
induced us to investigate the possibility of obtaining the
enantiomerically enriched isomers of cis-2 and trans-2, to
select those showing the most powerful and interesting
odour properties. Now we wish to report on the outcome of
this investigation, which is part of a research project aimed
at the preparation of the olfactory active stereoisomers of
commercial fragrances (9), via biocatalyzed methods.
Reduction of the carbonyl function of racemic
4
Results and discussion
(Scheme 2) gave lactone (4S,6S)-13, which was recovered in
pure form after column chromatography, and reduced with
LiAlH4 to give diol (1S,3R)-anti-11 (ee > 99%, de = 97%,
chiral HPLC). This latter was then converted into (2S,4R)-
cis-2 (ee > 99%, de = 98%, [ ]2D0 –54.1 (c = 1.05, CHCl3))
according to the mentioned procedure, via the corresponding
tosylate derivative (1S,3R)-anti-12.
Two different approaches to optically active Doremox®
isomers were chosen on the basis of our past experience:
(i) enantioselective synthesis based on bakers’ yeast (BY) re-
duction; (ii) lipase-mediated kinetic resolution of suitable
precursors.
In both cases the preferred isomer was produced enantio-
specifically, but with different diastereoselection: syn-
diastereoisomer prevailed when BY promoted the reduction
of the double bond, while anti-diastereoisomer was obtained
Bakers’ yeast approach
We had successfully developed synthetic methods for the
preparation of enantiomerically enriched rose oxide (10) and
Aerangis lactone (11), based on BY-enantiospecific and
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Can. J. Chem. Vol. 80, 2002
Scheme 3. (i) LiAlH4, THF, then AcOEt; (ii) NaBH4, MeOH–CH2Cl2; (iii) MeOH–HCl; (iv) LiAlH4, THF, then MeOH.
when the reduction of the carbonyl was involved. As for diol
anti-11, opposite enantioselection was observed: (1R,3S)-
anti-11 was the product of BY reduction of hydroxy alde-
hyde 3, while its enantiomer (1S,3R)-anti-11 was the result
of yeast fermentation of keto acid 6.2
tion mixture allowed us to detect cis-16 (25%) and trans-16
(20%), syn-11 (14%) and anti-11 (10%), (E)-8 (12%) and
(Z)-8 (6%) (20), and a complex system of compounds with
retention times and mass spectra resembling those of 17a
and 17b (12%). The reaction was then repeated using metha-
nol to consume the excess of LiAlH4 and the residue was
chromatographed, to yield a nearly 1:1 mixture of cis-16 and
trans-16 and a 2:1 mixture of syn-diol 11 and anti-diol 11.
The saturated diol fraction was enriched in the syn-
diasteroisomer (de = 83%) by column chromatography. An
analytical sample of trans-16 was obtained by careful col-
umn chromatography and recrystallization from ether. This
sample was reduced to syn-11 with NABH4 and converted
into methyl glycosides trans-18a and trans-18b with
MeOH–HCl.
Racemic diols anti-11 (de > 99%) and syn-11 (de = 83%)
were acetylated with Ac2O–Py, and the corresponding acetyl
derivatives anti-19 and syn-19 were submitted separately to
enzymic saponification, at pH 7.8 in the presence of lipase
PS. As for diacetate anti-19 (Scheme 4), the first enzymic
saponification (monitored by chiral HPLC) afforded mono-
acetate (1R,3S)-anti-20 showing 55% ee (chiral HPLC). This
latter was acetylated and submitted again to lipase-mediated
hydrolysis, to give (1R,3S)-anti-20 with ee = 95% (chiral
HPLC). Treatment with KOH in methanol gave (1R,3S)-
anti-11 (ee = 95%, chiral HPLC). Diacetate (1S,3R)-anti-19
(ee = 41%), chiral HPLC of the corresponding diol), recovered
Lipase-mediated kinetic resolution
A second approach to optically active Doremox® was in-
vestigated, to prepare all the four possible stereoisomers in
enantiomerically enriched form. For this purpose the prepa-
ration of the two racemic diols anti-11 and syn-11 was opti-
mized.
Lactone 7 was treated with lithium aluminum hydride in
THF (Scheme 3). When the reaction mixture was quenched
with ethyl acetate, a complex mixture of products was ob-
tained. The following compounds could be isolated and
identified: tetrahydropyranol cis-16 (1:1 mixture of the two
possible epimers at C-2, 40%), substituted tetrahydropyra-
nols 17a (11%) and 17b (10%),3 unsaturated diol (Z)-8 (8%)
(20), and diol anti-11 (12%). The structural assignment to
1
cis-16 was based on H NMR and mass spectrometry data,
and on its chemical reactivity; it afforded diol anti-11 upon
NaBH4 reduction, and it was transformed into the mixture of
the epimeric methyl glycosides cis-18a and cis-18b by treat-
ment with MeOH–HCl.
Low diastereoselection was obtained when hydroxy ester
6 was reduced (Scheme 3). GC–MS analysis of the reduc-
2 When unsaturated aldehyde 14 (18a) (E:Z, 2:1) (Scheme 1) was submitted to yeast fermentation, saturated alcohol (+)-(R)-15 (19) (ee 82%,
chiral HPLC) was obtained. BY reduction of the conjugated double bond thus showed the same preferred enantioselectivity in structurally
related compounds (CIP descriptors are different because the group priority changes from (E)-3 to 14).
1
3 The formation of derivatives 17a and 17b was unexpected and unusual. H NMR spectra showed that in both compounds the substituent
CH(OH)CH3 was located in the equatorial position (17a J(H-3,H-4) = 11.5 Hz, 17b J(H-2,H-3) = 8.9 Hz).
© 2002 NRC Canada

Brenna et al.
717
Scheme 4. (i) Acetic anhydride, pyridine; (ii) lipase PS,
THF–water, pH 7.8, 0.025 M NaOH; column chromatography;
(iii) KOH, MeOH; (iv) TosCl, pyridine, then MeONa in metha-
nol; (v) Jones’ reactive acetone.
Scheme 5. (i) Acetic anhydride, pyridine; (ii) lipase PS,
THF–water, pH 7.8, 0.025 M NaOH; column chromatography;
(iii) KOH, MeOH; (iv) TosCl, pyridine, then MeONa in metha-
nol; (v) Jones’ reactive acetone.
unreacted from the first saponification, was depleted of the
(1R,3S) enantiomer as much as possible by prolonged enzy-
mic reaction. Finally, it afforded diol (1S,3R)-anti-11 with
ee = 86% (chiral HPLC) by reaction with KOH in methanol.
The same procedure was applied to diacetate syn-19
(Scheme 5). (1S,3S)-syn-11 (ee = 72%, de = 70%) and
(1R,3R)-syn-11 (ee = 50%, de = 79%) were obtained from
monoacetate syn-20 and survived diacetate syn-19, respec-
tively.
The four enantiomerically enriched diols were treated
with tosyl chloride and pyridine, then with sodium methylate
in methanol, to promote ring closure. The following samples
of Doremox® were obtained: (i) (2R,4S)-cis-2 (from (1R,3S)-
anti-11): ee = 92%, de > 99% (chiral GC), [ ]2D0 +52 (c =
0.27, CHCl3); (ii) (2S,4R)-cis-2 (from (1S,3R)-anti-11): ee =
80%, de > 99% (chiral GC), [ ]2D0 – 42 (c = 1.2, CHCl3);
(iii) (2S,4S)-trans-2 (from (1S,3S)-syn -11): ee = 72%, de =
70% (chiral GC), [ ]2D0 + 14.6 (c = 0.3, CHCl3); this sample
contained 15% of (+)-cis-2 with ee = 73%; (iv) (2R,4R)-
trans-2 (from (1R,3R)-syn-11): ee = 50%, de = 77% (chiral
GC), [ ]2D0 – 9.8 (c = 1.15, CHCl3); this sample contained
11.5% of (–)-cis-2 with ee = 65%.
signed by chemical correlation on the basis of these data:
(i) H NMR spectra of cis-2 and trans-2 had been described,
1
so the relative configurations of Doremox® isomers and
those of the diol precursors could be defined; (ii) samples of
(–)-anti-11 (ee > 99%) and of (+)-syn-11 (ee = 50%, de =
79%) were oxidized to the corresponding keto acids upon
treatment with Jones’ reactive in acetone solution. These lat-
ter derivatives were purified by column chromatography of
the correponding methyl esters (diazomethane). In both
cases, (–)-(S)-10 (lit. value (21a) [ ]2D0 – 5.65 (c = 1.24, ben-
zene) for the (S)-isomer, ee = 90%; lit. value (21b) [ ]D20
+9.25 (neat) for the (R)-isomer, ee > 96%) was obtained
showing optical rotation values of –5.02 (c = 0.85, benzene;
prepared from anti-11) and –3.21 (c = 0.73, benzene; pre-
pared from syn-11). (R)-Configuration was assigned to C-3
in (–)-anti-11 and (+)-syn-11 (the CIP descriptor of the
stereogenic carbon atom changes because the order of group
priority is different). The absolute configurations of all the
derivatives involved in the synthetic scheme was then de-
duced.
Thus, it was possible to verify that lipase PS promoted the
saponification of both the diol isomers showing (S)-configu-
ration at the carbon atom nearer to the reactive site.
Configurational assignment
The absolute configurations of the two stereocentres of
diols anti-11 and syn-11 and of cis-2 and trans-2 were as-
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Can. J. Chem. Vol. 80, 2002
ganic layer was washed with a solution of ammonium chlo-
ride, dried (Na2SO4), and concentrated. Column chromatog-
raphy (hexane–EtOAc, 9:1) provided hydroxy ester 6
(16.7 g, 38%) and lactone 7 (17.7 g, 47%).
Olfactory descriptions
Olfactory evaluation of Doremox® samples gave the fol-
lowing results: (i) (2R,4S)-cis-2, ee = 92%, de > 99%: rose
oxide, diphenyl oxide, metallic, slightly plastic; (ii) (2S,4R)-
cis-2, ee = 80%, de > 99%: rose oxide, powerful, nice;
(iii) (2S,4S)-trans-2, ee = 72%, de = 70%: weak, rosy, plas-
6
GC–MS (tR = 21.80 min) m/z: 186 (M+ – 34) (50), 158
tic, citronellol,
a rose oxide note is also present;
1
(100), 129 (40), 77 (25). H NMR (CDCl3, ppm): 7.32 (m,
(iv) (2R,4R)-trans-2, ee = 50%, de = 77%: rosy, rose oxide,
metallic, off-note.
5H, C6H5), 5.76 (q, J = 1.1 Hz, 1H, H-C2), 4.89 (dd, J = 4.6,
8.1 Hz, 1H, H-C5), 3.68 (s, 3H, COOCH3), 2.53 (m, 2H,
CH2), 2.22 (d, J = 1.1 Hz, 3H, CH3-C=C).
Experimental
7
Lipase PS Pseudomonas cepacia (Amano Pharmaceuticals
Co., Japan) was employed in this work. GC–MS analyses
were performed on a HP 6890 gas chromatograph equipped
with a 5973 mass detector, using a HP-5MS column (30 m ×
0.25 mm × 0.25 m). The following temperature program
was employed: 60°C (for 1 min)/6°/min to 150°C (for
1 min)/12°/min to 280°C (for 5 min). Chiral GC analyses
mp 60°C. GC–MS (tR = 21.80 min) m/z: 188 (M+) (10),
1
105 (8), 82 (100). H NMR (CDCl3, ppm): 7.35 (m, 5H,
C6H5), 5.87 (m, 1H, H-C3), 5.37 (dd, J = 3.9, 11.8 Hz, 1H,
H-C6), 2.62 (ddm, J = 11.8, 18.0 Hz, 1H, H-C5), 2.42 (dd,
J = 3.9, 18.0 Hz, 1H, H-C5), 1.99 (m, 3H, CH3-C=C).
of Doremox® stereoisomers were performed on
a
(E)-3-Methyl-5-phenyl-2-pentene-1,5-diol ((E)-8)
A 1.5 M solution of diisobutyl aluminum hydride in tolu-
ene (69 mL, 0.103 mol) was added dropwise to a solution of
hydroxy ester 6 (10.0 g, 0.045 mol) in 100 mL toluene at
–10°C. The reaction was allowed to warm to 25°C, treated
with water, filtered through a Celite cake, and extracted with
ethyl acetate. The residue was chromatographed (hex-
ane:EtOAc, 6:4) to give unsaturated diol (E)-8 (6.82 g,
79%). GC–MS (tR = 20.89 min) m/z: 174 (M+ – 18) (0.04),
DeTBuSiBETA (086) 25 m × 0.25 mm column (Mega, It-
aly), installed on a DANI HT 86.10 gas chromatograph, with
the following temperature program: 45°C (3 )/5°C/min to
75°C/0.5°C/min to 100°C/10°C/min to 180°C (5 ): tR
(2S,4R)-1a = 45.4 min, tR (2R,4S)-1a = 46.5 min, tR
(2R,4R)-1b = 49.2 min, tR (2S,4S)-1b = 49.7 min. Chiral
HPLC analyses were performed on a Chiralcel OD column
(Daicel, Japan) installed on a Merck–Hitachi L-6200 appara-
tus: 0.6 mL min–1, UV detector (254 nm), hex-
ane:isopropanol (95:5). The following retention times were
observed: (1RS,3SR)-anti-19 (single peak) tR = 11.4 min;
(1R,3S)-anti-20 tR = 21.7 min; (1S,3R)-anti-20 tR = 28.9 min;
(1R,3S)-anti-11 tR = 29.8 min; (1S,3R)-anti-11 tR = 30.6 min;
1
107 (71), 105 (83), 68 (100). H NMR (CDCl3, ppm): 7.25
(m, 5H, C6H5), 5.50 (tq, J = 6.7, 1.2 Hz, 1H, H-C2), 4.76 (t,
J = 6.7 Hz, 1H, H-C5), 4.09 (m, 2H, CH2OH), 2.35 (d, J =
6.7 Hz, 2H, CH2), 1.71 (d, J = 1.2 Hz, 3H, CH3-C=C). Anal.
calcd. for C12H16O2: C 74.97, H 8.39; found: C 74.75,
H 8.53.
(1S,3S)-syn-19 tR = 10.6 min; (1R,3R)-syn-19 tR
=
11.1 min; (1S,3S)-syn-20 tR = 17.2 min; (1R,3R)-syn-20
tR = 23.9 min; (1R,3R)-syn-11 tR = 30.8 min; (1S,3S)-syn-11
tR = 41.9 min; (R)-15 tR = 14.9 min; (S)-15 tR = 17.2 min.
1H NMR spectra were recorded at room temperature (r.t.) on
(E)-5-Hydroxy-3-methyl-5-phenyl-pent-2-enal ((E)-3) (14)
Manganese(IV) oxide (1.5 equiv) was added to a solution
of unsaturated diol (E)-8 (6.70 g, 0.035 mol) in 50 mL DMF.
The suspension was heated at 80°C for 4 h, then filtered
poured into water, and extracted with EtOAc. The organic
phase was dried (Na2SO4), and concentrated in vacuo. The
residue was chromatographed (hexane–EtOAc, 7:3) to afford
(E)-3 (6.05 g, 91%). GC–MS (tR = 21.20 min) m/z: 190 (M+)
1
a Bruker AC-250 spectrometer (250 MHz H). The chemical
shift scale was based on internal tetramethylsilane. Optical
rotations were measured on a Dr. Kernchen Propol digital
automatic polarimeter. Microanalyses were determined on a
Carlo Erba 1106 analyzer. TLC analyses were performed on
Merck Kieselgel 60 F254 plates. All the chromatographic
separations were carried out on silica gel columns.
1
(0.01), 172 (6), 107 (92), 84 (100). H NMR (CDCl3, ppm):
9.99 (d, J = 7.9 Hz, 1H, CHO), 7.35 (m, 5H, C6H5), 5.95 (dt,
J = 7.9, 1.1, 1H, H-C2), 4.94 (dd, J = 4.9, 8.7 Hz, 1H, H-C5),
2.68 (dd, J = 14.0, 8.7 Hz, 1H, H-C4), 2.57 (dd, J = 14.0,
4.9 Hz, 1H, H-C4), 2.22 (d, J = 1.1 Hz, 3H, CH3-C=C).
The mixture of (E)- and (Z)-methyl 4-bromo-3-methyl-2-
butenoate (5) was prepared as described in ref. 12. The
monochloride mono methyl ester of 3-methyl glutaric acid
was prepared according to ref. 15. Aldehyde 14 was pre-
pared according to ref. 18a, and the diasteroisomeric excess
Methyl 3-methyl-5-oxo-5-phenyl-pentanoate (10) (16)
Aluminum trichloride (15.9 g, 0.12 mol) was added to a
solution of derivative 9 (17.8 g, 0.10 mol) in 300 mL ben-
zene at 10°C. The reaction mixture was refluxed for 2 h,
poured into ice and 10% HCl, and extracted with EtOAc.
The organic phase was dried (Na2SO4), concentrated, and
chromatographed (hexane–EtOAc, 95:5), to give keto ester
10 (14.1 g, 64%). GC–MS (tR = 21.01 min) m/z: 220 (M+)
(1.4), 189 (7.1), 120 (75), 105 (100). 1H NMR (CDCl3,
ppm): 7.97 (m, 2H, aromatic hydrogens), 7.40 (m, 3H, aro-
matic hydrogens), 3.67 (s, 3H, COOMe), 3.11 (dd, J = 16.0,
5.8 Hz, 1H), 2.84 (dd, J = 16.0, 7.3 Hz, 1H), 2.66 (m, 1H,
1
(33%) was determined on the basis of H NMR spectra of
(E)-14 and (Z)-14 in ref. 18b.
5-Hydroxy-3-methyl-5-phenyl-pent-2-enoic acid methyl
ester (6) (13) and 4-methyl-6-phenyl-5,6-dihydropyran-
2-one (7) (13)
A solution of bromo derivative 5 (38.4 g, 0.20 mol) and
benzaldehyde (2.12 g, 0.20 mol) in 100 mL THF was added
dropwise to a suspension of zinc (14.3 g, 0.22 mol) in
300 mL THF at 0°C. The reaction was refluxed for 2 h,
poured into ice, and extracted with ethyl acetate. The or-
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Brenna et al.
719
H-C3), 2.44 (dd, J = 15.4, 6.1 Hz, 1H), 2.31 (dd, J = 15.4,
7.3 Hz, 1H), 1.05 (d, J = 6.6 Hz, CH3).
calcd. for C14H20O3: C 71.16, H 8.53; found: C 70.89,
H 8.77.
An analytical sample of 17a was treated with Ac2O and
pyridine to give the corresponding diacetyl derivative. GC–
MS (tR = 25.56 min) m/z: 200 (M+ – 2 × 60) (47), 104 (100).
1H NMR (CDCl3, ppm): 7.32 (m, 5H, C6H5), 6.52 (d, J =
3.1 Hz, 1H, H-C2), 5.14 (dq, J = 3.1, 6.6 Hz, CHCH3OAc),
4.89 (dd, 1H, J = 12.0, 2.9 Hz, H-C6), 2.12 (m + s, 4H, H-C4 +
CH3COO), 2.04 (s, 3H, CH3COO), 1.95 (dt, J = 12.0,
2.9 Hz, 1H, H-C5), 1.72 (dt, J = 11.5, 3.1 Hz, H-C3), 1.40
(q, J = 12.0 Hz, 1H, H-C5), 1.32 (d, J = 6.6 Hz, 3H,
CH3CHOAc), 1.01 (d, J = 6.6 Hz, 3H, CH3-C4).
3-Methyl-5-oxo-5-phenyl-pentanoic acid (4) (17)
Keto ester 10 (14.0 g, 0.064 mol) was hydrolysed with
KOH (5.38 g, 0.096 mol) in 70 mL MeOH to afford, after
the usual work-up, keto acid 4 (12.4 g, 93%). 1H NMR
(CDCl3, ppm): 7.95 (m, 2H, aromatic hydrogens), 7.40 (m,
3H, aromatic hydrogens), 2.98 (m, 2H), 2.67 (m, 1H), 2.45
(m, 2H), 1.09 (d, J = 6.3 Hz, CH3).
LiAlH4 reduction of lactone 7
Procedure A
(2RS,3RS,4RS,6RS)-3-(1-Hydroxyethyl)-4-methyl-6-phenyl-
tetrahydro-2H-pyran-2-ol (17b, stereochemistry undefined at
the stereogenic carbon atom in the substituent group)
2.35 g (10%). GC–MS (tR = 24.15 min) m/z: 218 (M+ – 18)
A solution of lactone 7 (18.8 g, 0.10 mol), in 30 mL THF was
added dropwise to a suspension of LiAlH4 (7.6 g, 0.20 mol),
in 250 mL THF. The reaction mixture was stirred at r.t. for
12 h, then EtOAc was added to consume the excess LiAlH4.
The reaction mixture was poured into ice, extracted with
Et2O, dried (Na2SO4), and chromatographed (from hexane–
EtOAc (95:5) to hexane–EtOAc (1:1)). The following prod-
ucts, in order of progressive elution, were isolated.
1
(1.4), 200 (3.5), 174 (8.5), 159 (14), 104 (100). H NMR
(CDCl3, ppm): 7.30 (m, 5H, C6H5), 4.92 (d, J = 8.9 Hz, 1H,
H-C2), 4.50 (dd, 1H, J = 11.2, 2.2 Hz, H-C6), 4.11 (dq, J =
2.9, 6.7 Hz, CHCH3OH), 1.80 (dt, J = 12.6, 2.2 Hz, 1H, H-
C5), 1.66–1.25 (m, 3H, H-C5, H-C3, H-C4), 1.19 (d, J =
6.7 Hz, CH3CHOH), 0.98 (d, J = 6.7 Hz, 3H, CH3-C4).
Anal. calcd. for C14H20O3: C 71.16, H 8.53; found: C 71.55,
H 8.78.
(2RS,4RS,6RS)-4-Methyl-6-phenyl-tetrahydro-2H-pyran-2-ol
and (2RS,4SR,6SR)-4-methyl-6-phenyl-tetrahydro-2H-pyran2-
ol (cis-16, 1:1 mixture of the two epimers at C-2)
An analytical sample of 17b was treated with Ac2O and
pyridine to give the corresponding diacetyl derivative. GC–
MS (tR = 24.50 min) m/z: 200 (M+ – 2 × 60) (50), 104 (100).
1H NMR (CDCl3, ppm): 7.33 (m, 5H, C6H5), 5.94 (d, J =
8.5 Hz, 1H, H-C2), 5.23 (dq, J = 2.0, 6.7 Hz, CHCH3OAc),
4.61 (dd, J = 11.6, 2.0 Hz, 1H, H-C6), 2.14–2.02 (m + 2s,
7H, 1H + 2CH3COO), 1.94–1.4 (m, 3H), 1.29 (d, J =
6.9 Hz, 3H, CH3CHOAc), 1.17 (d, J = 6.2 Hz, 3H, CH3-C4).
7.68 g (40%), mp 67°C (diethyl ether). GC–MS (tR
=
19.34 min, single peak) m/z: 192 (M+) (1.7), 174 (13), 159
(17), 104 (100). 1H NMR (CDCl3, ppm): 7.32 (m, 10H,
2C6H5), 5.40 (m, 1H, H-C2 of one epimer), 4.98 (dd, 1H, J =
11.8, 2.1 Hz, H-C2 of one epimer), 4.74 (dd, 1H, J = 9.6,
2.1 Hz, H-C6 of one epimer), 4.74 (dd, 1H, J = 11.3, 1.7 Hz,
H-C6 of one epimer), 2.16 (m, 1H), 1.78 (m, 5H), 1.39–0.97
(m, 4H), 0.94 (d, J = 6.6 Hz, 3H, CH3 of one epimer), 0.90
(d, J = 6.6 Hz, 3H, CH3 of one epimer). Anal. calcd. for
C12H16O2: C 74.97, H 8.39; found: C 75.13, H 8.48.
(Z)-3-Methyl-5-phenyl-2-penten-1,5-diol ((Z)-8) (20)
1.53 g (8%). GC–MS (tR = 21.04 min) m/z: 174 (M+ – 18)
A sample of cis-16 was treated with MeOH–HCl to give
the mixture of the corresponding O-methyl glycosides cis-
18a and cis-18b (3:1 mixture of the two epimers at C-2).
GC–MS major epimer (tR = 17.61 min) m/z: 206 (M+) (2),
174 (41), 104 (94), 58 (100); minor epimer (tR = 18.17 min):
1
(2.8), 159 (3), 105 (86), 68 (100). H NMR (CDCl3, ppm):
7.29 (m, 5H, C6H5), 5.72 (t, J = 7.2 Hz, 1H, H-C2), 4.75 (dd,
J = 3.4, 9.4 Hz, 1H, H-C5), 4.09 (dd, J = 11.7, 7.2 Hz, 1H,
H-C1), 3.86 (dd, J = 11.7, 7.2 Hz, 1H, H-C1), 2.74 (dd, J =
13.4, 9.4 Hz, 1H, H-C4), 2.22 (dd, J = 13.4, 3.4 Hz, 1H,
H-C4), 1.81 (s, 3H, CH3-C3).
1
174 (M+ – 32) (3), 146 (27), 104 (100), 58 (50). H NMR
(CDCl3, ppm): 7.32 (m, 2C6H5), 4.90 (m, 1H of the major
epimer), 4.74 (dd, J = 11.8, 1.9 Hz, 1H of the major epimer),
4.48 (dd, J = 9.8, 1.9 Hz, 1H of the minor epimer), 4.43 (dd,
J = 11.3, 1.4 Hz, 1H of the minor epimer), 3.52 (s, OCH3 of
the minor epimer), 3.39 (s, OCH3 of the major epimer), 2.16
(m, 1H), 1.83 (m), 1.45–1.10 (m), 1.00 (d, J = 6.3 Hz, CH3
of the minor epimer), 0.93 (d, J = 6.8 Hz, CH3 of the major
epimer).
(1RS,3SR)-3-Methyl-1-phenyl-pentane-1,5-diol (anti-11)
2.33 g (12%), mp 76°C. GC–MS (tR = 20.89 min) m/z:
1
194 (M+) (9), 176 (15), 107 (100). H NMR (CDCl3, ppm):
7.33 (m, 5H, C6H5), 4.79 (m, 1H, H-C1), 3.69 (m, 2H,
CH2OH), 1.87 (m, 2H), 1.55 (m, 2H), 1.42 (m, 1H), 1.01 (d,
J = 6.4 Hz, 3H, CH3-C3). Anal. calcd. for C12H18O2: C 74.19,
H 9.34; found: C 73.93, H 9.15.
(2RS,3SR,4SR,6SR)-3-(1-Hydroxyethyl)-4-methyl-6-phenyl-
tetrahydro-2H-pyran-2-ol (17a, stereochemistry undefined at
the stereogenic carbon atom in the substituent group)
2.59 g (11%). GC–MS (tR = 24.12 min) m/z: 218 (M+ – 18)
(1.7), 200 (1), 174 (17), 159 (25), 104 (100). 1H NMR
(CDCl3, ppm): 7.28 (m, 5H, C6H5), 5.43 (d, J = 3.1 Hz, 1H,
H-C2), 5.02 (dd, 1H, J = 12.0, 2.9 Hz, H-C6), 4.02 (dq, J =
3.1, 6.7 Hz, 1H, CHCH3OH), 2.32 (m, 1H, H-C4), 1.84 (dt,
J = 12.0, 2.9 Hz, 1H, H-C5), 1.36 (q, J = 12.0 Hz, 1H, H-
C5), 1.29 (dt, J = 11.5, 3.1 Hz, H-C3), 1.12 (d, J = 6.7 Hz,
3H, CH3CHOH), 0.94 (d, J = 6.7 Hz, 3H, CH3-C4). Anal.
Procedure B
A solution of lactone 7 (18.8 g, 0.10 mol), in 30 mL THF
was added dropwise into a suspension of LiAlH4 (7.60 g,
0.20 mol), in 250 mL THF. The reaction mixture was stirred
at r.t. for 12 h, then MeOH was added to consume the excess
LiAlH4. The reaction mixture was poured into ice, extracted
with Et2O, dried (Na2SO4), and chromatographed (from hex-
ane–EtOAc (95:5) to hexane:EtOAc (1:1)). The following
products, in order of progressive elution, were isolated: cis-
16 (8.64 g, 45%), (Z)-8 (1.15 g, 6%), anti-11 (3.49 g, 18%).
© 2002 NRC Canada

720
Can. J. Chem. Vol. 80, 2002
cis-16 (8.50 g, 0.045 mol) was treated with NaBH4
Yeast reduction
(2.56 g, 0.067 mol) in 50 mL CH2Cl2–MeOH (2:1) solution,
to afford, after the usual work-up, anti-11 (7.59 g, 87%).
A suspension of bakers’ yeast (0.5 kg) and D-glucose
(0.4 kg) in tap water (1.5 L) was stirred for 30 min at 32°C.
A solution of the suitable substrate (0.03 mol) in ethanol
(20 mL) was then added. After 48 h at r.t., Celite (200 g)
was added, and the reaction mixture filtered, washing the
Celite pad with ethyl acetate. The filtrate was adjusted to
pH 4 with 2 N HCl, and extracted with ethyl acetate. The or-
ganic layer was dried (Na2SO4) and concentrated under re-
duced pressure. The residue was chromatographed on a
silica gel column. The following derivatives were obtained
upon BY reduction.
LiAlH4 reduction of hydroxy ester 6
Procedure A
The reduction of 6 (22.0 g, 0.10 mol), followed by treat-
ment with EtOAc, gave the following mixture of products
(GC–MS identification only): cis-16 (25%, tR = 19.35 min),
trans-16 (20%, tR = 19.59 min), syn-11 (14%, tR
=
20.80 min), anti-11 (10%, tR = 20.89 min), (Z)-8 (6%, tR =
21.03 min), (E)-8 (12.5%, tR = 21.19 min), unidentified
products 12%, 23.72–24.12 min.
(1S,3S)-3-Methyl-1-phenyl-pentane-1,5-diol ((1S,3S)-syn-11)
2.99 g (44%) (from (E)-3 (6.60 g, 0.035 mol)), ee > 99%
(chiral HPLC), de = 60% (GC–MS). The sample contained
1
20% of (1R,3S)-anti-11 (ee > 99%, chiral HPLC). H NMR
Procedure B
and GC–MS spectra were in agreement with those of
(±)-syn-11.
The reduction of 6 (22.0 g, 0.10 mol), followed by treat-
ment with MeOH, gave a residue which was chromato-
graphed, to give (after column chromatography) a 1:1
mixture of cis- and trans-16 (2.96 g, 15%), a 9:1 mixture of
(E)- and (Z)-8 (1.82 g, 9%), and a 2:1 mixture of syn- and
anti-11 (12.4 g, 64%).
(4S,6S)-4-Methyl-6-phenyl-tetrahydropyran-2-one (13) (23)
4.27 g (31%) (from 4). [ ]2D0 –12.1 (c = 1.26, CHCl3).
GC–MS (tR = 21.65 min) m/z: 190 (M+) (28), 104 (100), 56
1
(95). H NMR (CDCl3, ppm): 7.37 (m, 5H, C6H5), 5.31 (dd,
J = 3.7, 12.0 Hz, 1H, H-C6), 2.81 (m, 1H), 2.30–2.10 (m,
3H), 1.53 (m, 1H), 1.08 (d, J = 6.0 Hz, 3H, CH3-C4). This
derivative (4.20 g, 0.022 mol) was reduced with LiAlH4
(0.841 g, 0.044 mol) in 50 mL THF, to afford, after the usual
work-up, (1S,3R)-anti-11 (3.03 g, 71%), ee = 99% (chiral
HPLC), de = 99% (GC–MS). [ ]2D0 –60.2 (c = 1.05,
(2RS,4RS,6SR)-4-Methyl-6-phenyl-tetrahydro-2H-pyran-2-
ol and (2RS,4SR,6RS)-4-methyl-6-phenyl-tetrahydro-2H-pyran-
2-ol (trans-16, mixture of two epimers)
The 1:1 mixture of cis- and trans-16 (2.96 g) was
chromatographed (hexane–EtOAc, 9:1), to give, after crys-
tallization from ether, trans-16 (1.03 g), mp 72°C. GC–MS
(tR = 19.57 min (single peak)) m/z: 192 (M+) (3.3), 174 (42),
159 (83), 104 (100). 1H NMR (CDCl3, ppm): 7.35 (m,
2C6H5), 5.15 (m), 5.07 (dd, J = 9.1, 3 Hz, 1H), 4.74 (dd, J =
11.7, 2.3 Hz), 2.27 (m), 2.11–1.29 (m), 1.17 (d, J = 6.9 Hz,
2CH3). Anal. calcd. for C12H16O2: C 74.97, H 8.39; found:
C 75.26, H 8.11.
A sample of trans-16 was treated with MeOH–HCl, to af-
ford the mixture of the corresponding O-methyl glycosides
trans-18a and trans-18b (2:1 mixture of the two epimers at
C-2). GC–MS major epimer (tR = 17.88 min) m/z: 174 (M+ – 32)
1
CHCl3). H NMR and GC–MS spectra were in agreement
with those of (±)-anti-11.
(R)-3-Methyl-5-phenyl-pentan-1-ol ((R)-15)
2.99 g (29%) (from (E)-14 (de = 33%, 10.1 g, 0.058
mol)), ee = 82% (chiral HPLC). [ ]2D0 +11.2 (c = 11.4,
CHCl3) (lit. (19) [ ]2D0 –2 (neat) for the (S)-isomer). GC–
MS (tR = 16.60 min) m/z: 178 (M+) (30), 160 (35), 104
(91%), 91 (100). 1H NMR (CDCl3, ppm): 7.21 (m, 5H,
C6H5), 3.68 (m, 2H, CH2OH), 2.61 (m, 2H, CH2Ph), 1.62
(m, 3H), 1.49 (m, 2H), 0.98 (d, J = 6.0 Hz, 3H, CH3-C3).
(23), 146 (25), 104 (100), 58 (85); minor epimer (tR
=
(1RS,3SR)-Acetic acid 5-acetoxy-3-methyl-1-phenyl-pentyl
ester (anti-19)
18.53 min) m/z: 174 (M+ – 32) (4), 146 (21), 104 (100), 58
(50). 1H NMR (CDCl3, ppm): 7.35 (m, 2C6H5), 4.96 (dd, J =
3.9, 9.3 Hz), 4.78 (t, J = 3.9 Hz), 4.71 (m), 3.50 (s, OCH3 of
the minor epimer), 3.39 (s, OCH3 of the major epimer), 2.31
(m), 2.06–1.43 (m), 1.22 (d, J = 6.9 Hz, CH3 of the major
epimer), 1.21 (d, J = 6.7 Hz, CH3 of the minor epimer).
Diol anti-11 (11.4 g, 0.056 mol) was treated with 6 mL
Ac2O and 6 mL pyridine, to afford, after the usual work-up,
diacetate anti-19 (14.5 g, 92%). GC–MS (tR = 22.92 min)
m/z: 278 (M+) (1), 235 (31), 175 (92), 143 (75), 107 (100).
1H NMR (CDCl3, ppm): 7.30 (m, 5H, C6H5), 5.85 (dd, J =
4.6, 9.2 Hz, 1H, H-C1), 4.10 (m, 2H, CH2OAc), 2.06 (s, 3H,
CH3COO), 2.03 (s, 3H, CH3COO), 1.98 (m, 1H), 1.81–1.44
(m, 4H), 0.97 (d, J = 6.2 Hz, 3H, CH3-C3). Anal. calcd. for
C16H22O4: C 69.04, H 7.97; found: C 69.27, H 7.81.
(E)-3-Methyl-5-phenyl-2-pentene-1,5-diol ((E)-8)
Yield 1.82 g (9)%.
(1RS,3RS)-3-Methyl-1-phenyl-pentane-1,5-diol (syn-11)
12.4 g (64%), de = 33%. The de was increased by column
chromatography (hexane–EtOAc, 8:2), with syn-11 eluting
first. syn-11 with de = 83% was obtained (8.71 g, 70%).
GC–MS (tR = 20.80 min) m/z: 194 (M+) (7), 176 (9), 107
(1RS,3RS)-Acetic acid 5-acetoxy-3-methyl-1-phenyl-pentyl
ester (syn-19)
Diol syn-11 (8.60 g, 0.044 mol) was treated with 5 mL
Ac2O and 5 mL pyridine, to afford, after the usual work-up,
diacetate syn-19 (11.1 g, 90%). GC–MS (tR = 22.83 min) m/z:
1
(100). H NMR (CDCl3, ppm): 7.29 (m, 5H, C6H5), 4.81 (t,
1
J = 5.4 Hz, 1H, H-C1), 3.66 (m, 2H, CH2OH), 1.70 (m, 4H),
1.39 (m, 1H), 0.96 (d, J = 6.1 Hz, 3H, CH3-C3). Anal. calcd.
for C12H18O2: C 74.19, H 9.34; found: C 73.89, H 9.10.
235 (M+ – 43) (33), 175 (94), 143 (73), 107 (100). H NMR
(CDCl3, ppm): 7.30 (m, 5H, C6H5), 5.82 (t, J = 7.3 Hz, 1H,
H-C1), 4.06 (m, 2H, CH2OAc), 2.05 (s, 3H, CH3COO), 1.99
© 2002 NRC Canada

Brenna et al.
721
(s, 3H, CH3COO), 1.86–1.38 (m, 5H), 0.98 (d, J = 6.2 Hz,
3H, CH3-C3). Anal. calcd. for C16H22O4: C 69.04, H 7.97;
found: C 68.85, H 8.21.
(1S,3R)-3-Methyl-1-phenyl-pentane-1,5-diol ((1S,3R)-anti-
11)
Diacetate (1S,3R)-anti-19 (2.20 g, 7.91 mmol) was hydro-
lysed with KOH (0.644 g, 0.012 mol) in 10 mL MeOH, to
afford diol (1S,3R)-anti-11 (1.39 g, 91%), ee = 86% (chiral
HPLC), de > 99% (GC–MS). [ꢀ]2D0 –53.4 (c = 0.55, CHCl3).
1H NMR and GC–MS spectra were in agreement with those
of (±)-anti-11.
General procedure of lipase-mediated kinetic resolution
A solution of the suitable diacetate (10.0 g, 0.036 mol) in
2 mL THF was added to a suspension of lipase PS (5 g) in
100 mL water at pH 7.8 at room temperature. The pH was
kept constant by means of a pH-Stat. The reaction was mon-
itored by chiral HPLC. When the mono alcohol mono ace-
tate formed upon saponification reached ee ~ 50%, the
reaction was stopped. The mixture was filtered, extracted
with EtOAc, and chromatographed (hexane–EtOAc, 9:1).
The mono alcohol mono acetate was acetylated with Ac2O
and pyridine, and submitted again to enzymic saponification
to enhance ee.
(1S,3S)-3-Methyl-1-phenyl-pentane-1,5-diol ((1S,3S)-syn-
11)
Mono alcohol mono acetate (1S,3S)-syn-20 (1.30 g,
5.51 mmol) was hydrolysed with KOH (0.464 g, 8.26 mmol)
in 10 mL MeOH, to afford diol (1S,3S)-syn-11 (1.01 g, 95%),
ee = 70% (chiral HPLC), de = 72% (GC–MS). [ꢀ]2D0 –15.5
1
(c = 1.05, CHCl3). H NMR and GC–MS spectra were in
agreement with those of ((±)-syn-11.
(1R,3S)-Acetic acid 5-hydroxy-3-methyl-1-phenyl-pentyl es-
ter ((1R,3S)-anti-20) (from (±)-anti-19)
(1R,3R)-3-Methyl-1-phenyl-pentane-1,5-diol ((1R,3R)-syn-
11)
1.53 g (18%), ee = 95% (chiral HPLC), de > 99% (GC–
Diacetate (1R,3R)-syn-19 (2.30 g, 8.27 mmol) was hydro-
lysed with KOH (0.694 g, 0.012 mol) in 10 mL MeOH, to
afford diol (1R,3R)-syn-11 (1.41 g, 88%), ee = 50% (chiral
HPLC), de = 77% (GC–MS). [ꢀ]2D0 +11.05 (c = 1.05,
MS). [ꢀ]2D0 +67 (c = 1.4, CHCl3). GC–MS (tR = 21.73 min)
1
m/z: 193 (M+ – 43) (67), 175 (11), 107 (100). H NMR
(CDCl3, ppm): 7.30 (m, 5H, C6H5), 5.86 (dd, J = 4.9,
9.4 Hz, 1H, H-C1), 3.68 (m, 2H, CH2OH), 2.04 (s + m, 4H,
1H + CH3COO), 1.78–1.36 (m, 4H), 0.96 (d, J = 6.4 Hz,
3H, CH3-C3). Anal. calcd. for C14H20O3: C 71.16, H 8.53;
found: C 71.33, H 8.32.
1
CHCl3). H NMR and GC–MS spectra were in agreement
with those of (±)-syn-11.
General procedure for the preparation of Doremox®
p-Toluene-sulfonyl chloride (1.47 g, 7.73 mmol) was
added to a solution of the suitable diol (1.00 g, 5.15 mmol),
in 10 mL CH2Cl2 and 2 mL pyridine at 0°C. The reaction
mixture was stirred at room temperature for 3 h, then poured
into water and extracted with CH2Cl2. The residue, obtained
upon concentration, was dissolved in 10 mL MeOH, and
treated with MeONa in MeOH (1 M, 8 mL). The reaction
mixture was stirred at r.t. for 2 h, poured into water, and ex-
tracted with EtOAc. The organic phase was dried (Na2SO4),
concentrated, and chromatographed (hexane–EtOAc, 95:5),
to afford cis or trans-2.
(1S,3S)-Acetic acid 5-hydroxy-3-methyl-1-phenyl-pentyl es-
ter ((1S,3S)-syn-20) (from (±)-syn-19)
1.36 g (16%), ee = 72% (chiral HPLC), de = 70% (GC–
MS). [ꢀ]2D0 –19.2 (c = 0.92, CHCl3). GC–MS (tR
=
1
21.65 min) m/z: 193 (M+ – 43) (73), 175 (89), 107 (100). H
NMR (CDCl3, ppm): 7.32 (m, 5H, C6H5), 5.86 (dd, J = 6.8,
7.9 Hz, 1H, H-C1), 3.64 (m, 2H, CH2OH), 2.05 (s, 3H,
CH3COO), 1.85–1.30 (m, 5H), 0.97 (d, J = 6.5 Hz, 3H,
CH3-C3). Anal. calcd. for C14H20O3: C 71.16, H 8.53; found:
C 70.91, H 8.37.
The diacetate (recovered unreacted) was submitted again
to enzymic saponification to increase ee.
(2R,4S)-cis-2 (from (1R,3S)-anti-11 (1.1 g, 5.67 mmol))
0.668 g (67%), ee = 92%, de > 99% (chiral GC). [ꢀ]D20
+52 (c = 0.27, CHCl3). GC–MS (tR = 15.59 min) m/z: 176
(1S,3R)-Acetic acid 5-acetoxy-3-methyl-1-phenyl-pentyl es-
ter ((1S,3R)-anti-19) (from (±)-anti-19)
1
(M+) (100), 175 (90), 105 (73). H NMR (CDCl3, ppm):
2.30 g (23%), ee = 86% (chiral HPLC), de > 99% (GC–
7.31 (m, 5H, C6H5), 4.31 (dd, J = 1.9, 11.2 Hz, 1H, H-C2),
4.15 (ddd, J = 1.5, 4.2, 11.2, 1H, C-H6), 3.60 (m, 1H, H-C6),
1.82 (m, 2H), 1.58 (m, 1H), 1.26 (m, 2H), 0.98 (d, J =
6.2 Hz, 3H, CH3-C4).
1
MS). [ꢀ]2D0 – 45 (c = 1.18, CHCl3). H NMR and GC–MS
spectra were in agreement with those of (±)-anti-19.
(1R,3R)-Acetic acid 5-acetoxy-3-methyl-1-phenyl-pentyl es-
ter ((1R,3R)-syn-19) (from (±)-syn-19)
(2S,4R)-cis-2 (from (1S,3R)-anti-11 (1.30 g, 6.70 mmol))
0.778 g (66%), ee = 80%, de > 99% (chiral GC). [ꢀ]D20
– 42 (c = 1.2, CHCl3). 1H NMR and GC–MS spectra were in
agreement with those of (+)-cis-2.
2.38 g (28%), ee = 50%, de = 79%. [ꢀ]2D0 +13.5 (c =
1
1.51, CHCl3). H NMR and GC–MS spectra were in agree-
ment with those of (±)-syn-19.
(1R,3S)-3-Methyl-1-phenyl-pentane-1,5-diol ((1R,3S)-anti-
11)
(2S,4S)-trans-2 (from (1S,3S)-syn-11 (0.981 g, 5.05 mmol))
0.577 g (65%), ee = 72%, de = 70% (chiral GC). [ꢀ]D20
+14.6 (c = 0.3, CHCl3); this sample contained 13% of
(+)-cis-2 and 2% of (–)-cis-2. GC–MS (tR = 16.05 min) m/z:
Mono alcohol mono acetate (1R,3S)-anti-20 (1.50 g,
6.36 mmol) was hydrolysed with KOH (0.533 g, 9.54 mmol)
in 10 mL MeOH, to afford diol (1R,3S)-anti-11 (1.16 g,
94%), ee = 95% (chiral HPLC), de > 99% (GC–MS). [ꢀ]D20
1
176 (M+) (100), 175 (89), 105 (80). H NMR (CDCl3, ppm):
7.31 (m, 5H, C6H5), 4.67 (dd, J = 3.1, 9.6 Hz, 1H, H-C2),
3.83 (m, 2H, CH2-O), 2.10 (m, 1H), 1.92 (m, 2H), 1.61
(m, 1H), 1.34 (m, 1H), 1.17 (d, J = 7.1 Hz, 3H, CH3-C4).
1
+54.8 (c = 0.5, CHCl3). H NMR and GC–MS spectra were
in agreement with those of (±)-anti-11.
© 2002 NRC Canada

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Can. J. Chem. Vol. 80, 2002
(2R,4R)-trans-2 (from (1R,3R)-syn-11 (1.30 g, 6.70 mmol))
0.743 g (63%), ee = 50%, de = 77% (chiral GC). [ ]2D0 –9.8
(c = 1.15, CHCl3); this sample contained 9.5% of (–)-cis-2
and 2% of (+)-cis-2. H NMR and GC–MS spectra were in
agreement with those of (+)-trans-2.
manding requisites on the substrate acceptance, but their
stereochemical course is sometimes less satisfactory, and
strongly dependent on structural factors.
1
The unusual behaviour of hydroxy ester 6 and lactone 7
under hydride reduction was fully described. Lactols were
isolated, as well as products of a diastereoselective addition
of some intermediates on EtOAc, followed by reduction.
Olfactory evaluation of optically enriched Doremox sam-
ples clearly showed that (2S,4R)-cis-2 is the nicest and the
most powerful isomer of the series. This stereoisomer, inci-
dentally, has the same absolute configuration of the most ap-
preciated of rose oxide isomers (22) (i.e., (2S,4R)-cis-1).
(2S,4R)-cis-2 (from (1S,3R)-anti-11 (1.50 g, 7.73 mmol, ob-
tained by reduction of (4S,6S)-13))
0.925 g (68%), ee = 98%, de > 99% (chiral GC). [ ]D20
54.1 (c = 1.05, CHCl3). H NMR and GC–MS spectra were
in agreement with those of (+)-cis-2.
–
1
(2S,4S)-trans-2 (from (1S,3S)-syn-11 (obtained by BY reduc-
tion of (E)-3))
ee = 99%, de = 72% (chiral GC). [ ]2D0 +18.1 (c = 0.75,
CHCl3); this sample contained 14% of (+)-cis-2 with ee >
Acknowledgement
1
COFIN-Murst is acknowledged for financial support. The
authors would like to thank Dr. Philip Kraft and Mrs. Caro-
line Denis (Givaudan Dübendorf AG, Fragrance Research)
for the olfactory descriptions of Doremox® samples.
99%. H NMR and GC–MS spectra were in agreement with
those of (+)-trans-2.
Configurational assignment
Two samples of (–)-anti-11 (ee = 86%, de > 99%) and
(+)-syn-11 (ee = 50%, de = 79%) were oxidized with Jones’
reagent in acetone. The corresponding keto acids were
treated with diazomethane in Et2O, and the corresponding
methyl ester derivatives were purified by column chromatog-
raphy (hexane). The following samples of keto ester 10 were
obtained: (i) (–)-10 (from (–)-anti-11): chemical purity (GC–
MS) = 98%. [ ]2D0 –5.02 (c = 0.85, benzene) lit. value (21a)
[ ]2D0 –5.65 (c = 1.24, benzene) for (S)-isomer ee = 90%; lit.
value (21b) [ ]2D0 +9.25 (neat) for (R)-isomer ee > 96%;
(ii) (–)-10 (from (+)-syn-11): chemical purity (GC–MS) =
97%. [ ]2D0 –3.21 (c = 0.73, benzene).
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Conclusion
The preparation of the four stereoisomers of Doremox® in
enantiomerically enriched form was accomplished. BY
reduction of suitable precursors 3 and 4 resulted in enantio-
specific and highly diastereoselective compounds. Diol pre-
cursors of (–)-cis-2 (ee > 99%, de = 98%) or of (+)-trans-2
(ee > 99%, de = 72%) were obtained when a carbonyl or a
carbon–carbon double bond was reduced by yeast, under the
influence of a preexisting stereocentre in position . Thus, an
interesting, unpredictable stereochemical feature of BY re-
duction was highlighted.
Lipase PS-mediated kinetic resolution of diol anti-11 and
syn-11 was less efficient, but it allowed us to obtain both the
enantiomers of the cis and trans series. The high reactivity
of primary acetate groups towards saponification prevented
the accomplishment of higher enantiomeric excesses. How-
ever, the enzymic reaction of diacetate derivatives enriched
in the most reactive enantiomer allowed us to reach quite
satisfactory enantiomeric excesses. Biocatalyzed reactions
are once again the most effective in the optical activation of
such scarcely functionalised substrates as diols anti-11 and
syn-11.
The whole work put into evidence the supremacy of yeast
reduction with respect to lipase-mediated hydrolysis. Once
the substrate has been accepted by yeast, the whole-cell
reductive system always assures enantiospecific transforma-
tions, which greatly compensate for the troublesome work-
up. Lipases are of much wider application, showing less de-
© 2002 NRC Canada

Brenna et al.
723
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© 2002 NRC Canada