Preparation of the Enantiomerically Enriched Isomers of the Odorous Cyclic Ethers Clarycet, Florol, and Rhubafuran by Enzymatic Catalysis

Article abstract of DOI:10.1002/hlca.200490075

All the enantiomerically enriched stereoisomers of Clarycet (1), Florol (2), and Rhubafuran (3) were prepared by biocatalysis routes. Their absolute configurations were established, and their olfactory properties were fully evaluated.

Full text of DOI:10.1002/hlca.200490075

Helvetica Chimica Acta Vol. 87 (2004)
765
Preparation of the Enantiomerically Enriched Isomers of the Odorous Cyclic
¾
¾
¾
Ethers Clarycet , Florol , and Rhubafuran by Enzymatic Catalysis
by Agnese Abate, Elisabetta Brenna*, Giovanni Fronza, Claudio Fuganti, Francesco G. Gatti, Stefano Serra,
and Enrica Zardoni1)
Dipartimento di Chimica, Materiali, Ingegneria Chimica, Politecnico di Milano, ed Istituto CNR per la Chimica
del Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano
To the memory of Enrica Zardoni
¾
¾
¾
All the enantiomerically enriched stereoisomers of Clarycet (1), Florol (2), and Rhubafuran (3) were
prepared by biocatalysis routes. Their absolute configurations were established, and their olfactory properties
were fully evaluated.
Introduction. One of the main goals of fragrance industry is to find more-intense
and more long-lasting odorous molecules to be used as alternatives to known products.
The target is to obtain powerful compounds that can satisfy the global demand in
reduced quantities. Lower volumes imply less impact on health and the environment
and simpler registration [1]. Possible approaches to molecules with enhanced odor
potency are the discovery of new compounds, may be upon Nature inspiration, or the
investigation of the odor properties of all the possible isomers of known chiral odorants.
For the last few years, we have been preparing the enantiomerically pure isomers of
commercial chiral fragrances to establish the real odor vectors. This systematic work
gave us the chance to highlight examples of the different odor thresholds shown by
¾
enantiomers: (‡)-Florhydral is 25 times more potent than its enantiomer [2]; (‡)-g-
ionone is much stronger than (À)-g-ionone, with an odor threshold of 0.07 ng/l vs.
11 ng/l [3].
We now wish to report the preparation of all enantiomerically pure isomers of the
¾
¾
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floral odorants Clarycet (1), Florol (2), and Rhubafuran (3)2) prepared by
biocatalysis routes. These fragrances are commercialized as mixtures of two racemic
¾
diastereoisomers. Clarycet (IFF) is described to have a −herbal floral, rosy odor with a
¾
dried fruitiness and a suggestion of clary sage×. Florol (Firmenich) is −fresh, soft, with a
natural floral note; it can be used in almost all perfume types where it gives elegant
¾
floral diffusion without changing the character of the fragrance×. Rhubafuran (Quest
International) is a −grapefruit fragrance with rhubarb undertones×.
Results and Discussion. Syntheses. As for the synthesis of the two tetrahydropyr-
anyl ethers, we envisaged hydroxy ketones 4 and 5 as starting materials to be prepared
1
)
)
21st May 1976 28th February 2003
2
For previously reported syntheses of mixture of the two racemic diastereoisomers of tetrahydro-4-methyl-
2-(2-methylethyl)-2H-pyran-4-ol, and tetrahydro-4-methyl-2-propyl-2H-pyran-4-ol, see [4]; for the two
racemic diastereoisomers of tetrahydro-2,4-dimethyl-4-phenyl-furan, see [5].

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Helvetica Chimica Acta Vol. 87 (2004)
in enantiomerically pure form. Aldol reaction is a powerful tool in synthetic chemistry,
and great effort is devoted to find new efficient chiral catalysts to optimize useful
enantioselective modifications [6]. Biochemical methods have also been developed to
prepare enantiomerically enriched aldols [7]. We have recently exploited the lipase-
mediated transesterification of racemic hydroxy ketone 6 to prepare a suitable building
¾
block for the synthesis of the enantiomerically pure isomers of the odorant Floropal
[8]. We used the same strategy to synthezise enantiomerically enriched 1,3-dioxane
¾
odorants related to Floropal and, thus, submitted hydroxy ketones 7 11 to lipase-
catalyzed acetylation (Table) [9].
Table. Lipase-Mediated Transesterification for the Synthesis of Enantiomerically Enriched Odorants
Substrate
Enzymea)
Acetate (ee [%]), Chemical yield [%]
Alcohol (ee [%]), Chemical yield [%]
4
5
6
7
8
9
CCL
(S)(60), 18
(S)(95), 30
(R)(97), 33
(R)(96), 41
(R)(86), 28
(R)(46)
(R)(98), 39
Racemic
Racemic
Racemic
lipase PS
lipase PS
lipase PS
lipase PS
lipase PS
PPL
(R)(91), 35
(S)(93), 37
(S)(94), 37
(S)(50), 55
(S)(82)
(S)(76), 33
Racemic
Racemic
10
11
PPL
PPL
a) CCL ˆ Candida cylindracea3) lipase; lipase PS ˆ Pseudomonas cepacia lipase; PPL ˆ porcine pancreas lipase.
On the basis of our previous experience, we investigated the lipase-mediated
acetylation of 4 and 5 in tBuOMe solution, using vinyl acetate as an acyl donor. Lipase
PS catalyzed the enantioselective acetylation of derivative 5 to afford the correspond-
ing acetate (S)-12 (30% yield) with an ee of 95% (Scheme 1). A rather slow
enrichment of the starting alcohol led us to recover hydroxy ketone (R)-5 showing an
ee of 91% (35% yield). Different results were obtained with racemic 4. Only CCL
(Candida cylindracea3) lipase) promoted the acetylation of 4 with low enantioselec-
tivity. Acetate (S)-13 (18% yield) showed an ee of 60%. Further enrichment was
3
)
A more-common recent name for Candida cylindracea is Candida rugosa.

Helvetica Chimica Acta Vol. 87 (2004)
767
obtained by submitting (S)-13 (60% ee) to biocatalyzed hydrolysis in H2O/THF
solution at pH 7.8 in the presence of CCL. Alcohol (S)-4 (67% yield) was recovered
with an ee of 80%. A striking influence of the structure on the steric course of lipase
acetylation was thus observed. The branched chain of hydroxy ketone 5 seems to be a
favorable structural feature, and acetylation proceeds with high enantioselectivity. (S)-
4 and (S)-5 had been previously prepared by enantioselective aldol reaction with an ee
of 58 89% [10 12] and 73 84% [12][13], respectively.
Scheme 1
i) tBuOMe, vinyl acetate, lipase; column chromatography. ii) THF/H2O, pH 7.8, CCL.
The Table shows that rather high ee values can be achieved with this procedure of
biocatalytic resolution of hydroxy ketones, characterized by the easy handling of
largely available lipases. While we were preparing the manuscript of this work, a paper
appeared describing the enzymatic kinetic resolution of some other b-hydroxy ketones
[14], completing a previous investigation of a few aromatic aldols [15]. These data,
combined with our results, highlight the synthetic potentiality of lipase resolution of
racemic hydroxy ketones, which can be employed as an alternative to enantioselective
aldol reactions catalyzed by chiral catalysts.
Enantiomerically enriched hydroxy ketones (S)-4 (80% ee), (R)-5 (91% ee), and
acetate (S)-12 (95% ee) were treated with allylmagnesium bromide in THF to afford
diols (4RS,6S)-14a (72% yield), (4RS,6R)-15a (76% yield), and (4RS,6S)-15a (71%
yield), respectively, all as mixtures of two diastereoisomers (Scheme 2). These latter
derivatives were acetylated and submitted to ozonolysis in CH2Cl2/MeOH. After
quenching with NaBH4 and saponification, triols (3RS,5S)-16b (65% yield from
(4RS,6S)-14a), (3RS,5R)-17b (63% yield from (4RS,6R)-15a), and (3RS,5S)-17b (70%
yield from (4RS,6S)-15a) were obtained. Reaction with TsCl in pyridine allowed us to
isolate the following cyclized compounds directly, each one as a mixture of two
diastereoisomers: (2S,4RS)-18, (2R,4RS)-2, and (2S,4RS)-2 (Scheme 2). The diaster-
eoisomers of each mixture could be separated by column chromatography to afford the
following products: (2S,4R)-18 (> 99% de, 80% ee, 39% yield), (2S,4S)-18 (> 99% de,
80% ee, 31% yield), (2R,4R)-2 (> 99% de, 91% ee, 30% yield), (2R,4S)-2 (96% de,
91% ee, 37% yield), (2S,4R)-2 (> 99% de, 95% ee, 35% yield), and (2S,4S)-2 (> 99%
de, 95% ee, 29% yield). Treatment of (2S,4R)-18 and (2S,4S)-18 in refluxing Ac2O in
the presence of NaOAc gave (2S,4R)-1 (76% yield) and (2S,4S)-1 (74% yield),
respectively (Fig. 1).

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 2
i) Allyl magnesium bromide, THF. ii) Ac2O, pyridine. iii) O3, CH2Cl2/MeOH; then NaBH4. iv) KOH, MeOH.
v) TsCl, pyridine.
Fig. 1. Synthesized odorants 1 and 2
The CCL-mediated acetylation of (Æ)-4 was too slow to allow recovery of the
enantiomerically enriched isomer (R)-4, thus a different route to the (2R)-configured
¾
Clarycet diastereoisomers was devised (Scheme 3). The mixture of the two
diastereoisomeric triols (3RS,5S)-16b was treated with lipase PS in tBuOMe and vinyl
acetate to afford the two diastereoisomeric monoacetates (3RS,5S)-19 (78% yield).
These latter derivatives were treated with TsCl in pyridine to give (3RS,5S)-20, which
was then submitted to saponification with 10% NaOH solution in EtOH. Ring closure
occurred with inversion of configuration at C(2), and a mixture of the two

Helvetica Chimica Acta Vol. 87 (2004)
769
Scheme 3
i) Lipase PS, tBuOMe, vinyl acetate. ii) TsCl, pyridine. iii) 10% NaOH soln., EtOH.
diastereoisomers (2R,4RS)-18 was obtained. The two diasteroisomers were separated
by column chromatography (30% and 38% yield) and submitted separately to
acetylation in refluxing Ac2O in the presence of NaOAc to give the two enantiomeri-
¾
cally enriched Clarycet isomers (2R,4S)-1 (69% yield) and (2R,4R)-1 (64% yield)
(Fig. 1).
¾
As for the synthesis of the four Rhubafuran stereoisomers, we employed hydroxy
ketone 6 as a starting material. Addition of methylmagnesium bromide, CrO3
oxidation, and subsequent dehydration afforded ketone 21 which was reduced to
allylic alcohol (E)-22 [16] (Scheme 4). This latter was submitted to lipase-PS
acetylation, and after 72h, acetate ( R,E)-23 (> 99% ee, 36% yield) and alcohol
(S,E)-22 (> 99% ee, 37% yield) were isolated after column chromatography. (R,E)-
and (S,E)-22 were treated with triethyl orthoacetate in the presence of a catalytic
amount of propanoic acid (Scheme 5). Distillation in vacuo of the reaction mixture,
followed by saponification, allowed us to isolate the two enantiomeric acids (R,E)- and
Scheme 4
i) MeMgBr, THF. ii) CrO3, acetone. iii) 10% HCl soln., THF. iv) NaBH4, CH2Cl2/MeOH. v) Lipase PS,
tBuOMe, vinyl acetate; column chromatography.
Scheme 5
i) Triethyl orthoacetate, propanoic acid; NaOH, H2O/EtOH. ii) Et3N, ClCOOEt; then MeMgCl, THF, À208.
iii) O3, CH2Cl2/MeOH.

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Helvetica Chimica Acta Vol. 87 (2004)
(S,E)-24 (64% and 60% yield). Treatment with ethyl carbonochloridate in THF
solution in the presence of Et3N gave a mixed anhydride, which was converted into
ketones (R,E)- and (S,E)-25 (69% and 67% yield) by addition of methylmagnesium
chloride at À208. Ozonolysis, followed by NaBH4 quenching, afforded diols (2S,4RS)-
and (2R,4RS)-26, respectively. Each mixture of diastereoisomers was submitted to
column chromatography, and the four isomers of diol 26 were obtained as pure
compounds (28 35% yield). Unfortunately, when the diastereoisomerically pure diols
26 were treated with triphenylphosphine and N-bromosuccinimide (NBS), or reacted
¾
with TsCl and pyridine, mixtures of Rhubafuran diastereoisomers were obtained. The
steric hindrance of the stereogenic C-atom next to the primary OH group seems to
make its reaction with NBS or TsCl quite difficult, and the reaction of the secondary
OH group becomes competitive.
¾
As in the case of the Clarycet isomers, we tried to selectively convert the primary
OH group to an acetate ester by submitting the four enantiomerically pure stereo-
isomers of diol 26 to enzyme-mediated acetylation in the presence of lipase PS in
separate experiments. The following results were obtained (Scheme 6): diols (2R,4S)-
26 and (2S,4R)-26 gave, after 8 days, a 1:1 mixture of the two possible monoacetates,
Scheme 6
t
i) Lipase PS, BuOMe, vinyl acetate. ii) TsCl, pyridine. iii) KOH, MeOH. iv) PPh3, NBS, CH2Cl2.

Helvetica Chimica Acta Vol. 87 (2004)
771
which could not be separated by column chromatography. Diols (2R,4R)-26 and
(2S,4S)-26 gave, after 5 days, a 1:1 mixture of the two monoacetates (2R,4R)-27/
(2R,4R)-28 (which could be separated by column chromatography, 35% and 32%
yield) and the single monoacetate (2S,4S)-27 (44% yield), respectively. Even enzymes
did not show a definite preference for the hindered primary OH group of this kind of
substrates. Reaction with TsCl in pyridine, followed by saponification with 10% NaOH
¾
solution in EtOH, afforded the following samples of Rhubafuran : (2R,4R)-3 (84% de,
> 99% ee, 50% yield from (2R,4R)-28), (2S,4R)-3 (66% de, > 99% ee, 56% yield from
(2R,4R)-27), (2R,4S)-3 (78% de, > 99% ee, 49% yield from (2S,4S)-27). The
preparation of the fourth isomer was accomplished by reaction of (2S,4S)-26 with
NBS and Ph3P (60% de, > 99% ee, 67% yield).
Configuration Assignment. The absolute configuration (S) of dextrorotatory
hydroxy ketone 4 is known from the literature [10][12][17] (see also Exper. Part).
Alcohol 4 (80% ee), obtained by enzyme-mediated hydrolysis of acetate 13, prepared
in turn by CCL acetylation of (Æ)-4, showed a positive [a]D; thus, (S) configuration
could be assigned to the enantiomer of 4 converted by CCL to the acetate derivative.
¾
The relative configurations of the two stereogenic C-atoms in Clarycet isomers were
established by NOE experiments. When the Me group at C(4) in (2R,4R)-1 was
irradiated, NOE effects were observed on HaxÀC(2) (4%) and HaxÀC(6) (8%), thus
showing a trans arrangement of MeÀC(4) and PrÀC(2). The cis relationship between
the Me group and the aliphatic chain in the corresponding diastereoisomer was
confirmed by submitting (2R,4S)-1 to NOESY experiments in C6D6 solution; no NOE
effects were observed between MeÀC(4) and HaxÀC(2) and HaxÀC(6), respectively.
As for dextrorotatory hydroxy ketone 5, the (S) configuration had been assigned in
the literature by analogy to 4 [12] (see also Exper. Part). The alcohol 5 left unreacted by
lipase PS in the enzyme-mediated acetylation of (Æ)-5 was found to be levorotatory.
Thus, (S)-configuration was assigned to the enantiomer of 5 converted by lipase PS
into the acetate derivative. The trans arrangement of the MeÀC(4) and
Me2CHCH2ÀC(2) in (2R,4R)-2 was shown by NOESY experiments (NOEs
MeÀC(4)/HaxÀC(2) and HaxÀC(6). No NOE effects were observed between
MeÀC(4) and HaxÀC(2) and HaxÀC(6) in the case of (2R,4S)-2, thus confirming this
assignment.
The absolute configuration (S) of levorotatory allylic alcohol 22 had been
established by chemical correlation [16]. Thus (R) configuration was assigned to the
enantiomer of 22 converted by lipase PS into the acetate derivative. The relative
¾
configuration of the two stereogenic C-atoms in Rhubafuran samples was established
by NOE experiments. When MeÀC(4) of (2R,4R)-3 was irradiated, NOE effects were
observed on HÀC(2) (5.9%) and both HÀC(3) (3.1 and 4.4%), thus showing a trans
arrangement of MeÀC(4) and MeÀC(2). The cis relationship between the two Me
groups in the corresponding diastereoisomer was confirmed by submitting (2R,4S)-3 to
NOE experiments (no NOE MeÀC(4)/HÀC(2)).
Olfactory Evaluation. All the samples were submitted to olfactory evaluation
(Givaudan perfumers) with the following results:
(2S,4S)-1: Green, fresh, earthy, fruity (sage), dry down odorless.

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Helvetica Chimica Acta Vol. 87 (2004)
(2S,4R)-1: Floral, agrestic, fruity, touch acetic-green-tobacco, dry down slightly
fruity, but very weak.
(2R,4R)-1: Pine, pine oil, terpenic, woody, dry down dusty dirty.
(2R,4S)-1: Fruity, rosy, rose ketone, good, touch earthy, dry, sweet, woody, sage, dry
down floral-sage.
¾
(2R,4R)-2: Most pronounced and most intense Florol stereoisomer (odor
threshold 1.21 ng/l air). Fresh, soft, sweet, and natural floral odor reminiscent of
muguet with some rose oxide side note and earthy nuances.
¾
(2S,4S)-2: Second intense Florol stereoisomer (odor threshold 26 ng/l air), but
already much weaker. Similar fresh-floral note as the enantiomer, but less sweet and
also more linalool-type, more herbaceous, and more earthy in tonality.
¾
(2R,4S)-2: The second weakest in the series of Florol stereoisomers (odor
threshold 520 ng/l air). Relatively weak, mainly fruity, grape-like, but also reminiscent
of linalyl acetate and clary sage oil, with some nuances of dry herbs.
(2S,4R)-2: Odorless on GC olfactometry (odor threshold > 600 ng/l air). The
¾
weakest of all Florol stereoisomers. Very weak in odor, mainly linalool and coumarine
like, with some citric and hesperidic nuances.
(2R,4R)-3: Nuts, acidic, animalic, slightly rhubarb.
(2S,4R)-3: Citric, rhubarb, slightly green, slightly animalic.
(2S,4S)-3: Grapefruit-like, bitter, cassis, slightly oxane-like and reminiscent of
dimethyloctenone. Dry down (24 h) bitter, grapefruit, oxane.
(2R,4S)-3: The most pleasant one, floral, linalool-like, rhubarb and citrus, green,
slightly eucalyptus.
(2R,4S)-3, followed by its enantiomer, are the closest to the commercial
¾
Rhubafuran .
Conclusions. The olfactory evaluations reported in this study highlight the effect
of configuration both on odor quality and odor thresholds.
As for Clarycet¾, the single enantiomer (2R,4S)-1 has a nice floral odor, which
makes it distinguished from the other stereoisomers. This latter can be related to the
best isomers of other tetrahydropyran fragrances, such as (2S,4R)-rose oxide and
¾
(2S,4R)-Doremox [18] (Fig. 2), which have a cis diequatorial arrangement of the
MeÀC(4) and the substituent at C(2), just as in (2R,4S)-1.
¾
A gradual variation of odor intensity was noticed in the four Florol isomers, from
1.21 ng/l of (2R,4R)-2 to more than 600 ng/l of (2S,4R)-2. The two enantiomers of the
diastereoisomer bearing the OH group and the isobutyl chain in equatorial positions
¾
are decidedly the most intense, and are responsible for the odor of commercial Florol .
¾
The same is true also for Rhubafuran : the two enantiomers of just one
diastereoisomer, in particular the one bearing the Me groups on the same side, are
¾
the real vectors of Rhubafuran fragrance. This latter can be structurally correlated to
¾
the odorant Floropal by removing the acetal MeÀCH moiety and replacing the O-
atom by a CH2 unit (Fig. 2). The same relative configuration is shown by the best
diastereoisomer of both the odorants.
The observed stereoselective bioaccumulation of certain chiral odorants [19], the
increasing need to control and limit fragrances considered to be allergens [20], the
necessity to reduce the global volume of chemicals employed in fine and functional

Helvetica Chimica Acta Vol. 87 (2004)
773
Fig. 2. Comparison of the structures of some odorants
perfumery make the investigation of the odor properties of chiral commercial odorants
highly necessary. The preparation of enantiomerically pure single isomers and the
establishment of their absolute configuration help to determine the effective odor
vector and to implement the study of structure odor relationship. For this purpose,
both enantiomers of every single stereoisomer are to be prepared. Biocatalyzed kinetic
resolutions are particularly useful as they provide both enantiomers of a chiral
molecule within a single step, unlike most of the methods of asymmetric synthesis that
require the optimization of both enantiomers of the chiral auxiliary. Classical methods
of resolution are difficult to apply to fragrance molecules, which are usually poorly
functionalized. The work we have been doing in recent years shows the wide
applicability and synthetic versatility of enzymatic procedures in the field of fragrance
chemistry. Lipase-mediated resolutions are characterized by easy and rapid applica-
tions and allow the preparation of good quantities of enantiomerically pure isomers.
The authors are indebted to Dr. Philip Kraft and Mr. Jean-Jacques Rouge (Givaudan Schweiz AG,
Fragrance Research, Switzerland) for the odor descriptions. COFIN-Murst is acknowledged for financial
support.

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Helvetica Chimica Acta Vol. 87 (2004)
Experimental Part
General. Hydroxy ketones 4 [21], 5 [22], and 6 [23] were prepared according to the literature by aldol
condensation. 2-Phenylpentane-2,4-diol was prepared according to [8], and was then oxidized with CrO3 in
acetone at r.t. The resulting ketone was dehydrated to compound 21 according to [24]. Reduction of 21 to 224)
was performed according to [26]. Lipase PS from Pseudomonas cepacia (Amano Pharmaceuticals Co., Japan)
and Candida rugosa3) lipase (Sigma) were employed in this work. Chiral GC: Chirasil DEX-CB column (25 Â
0.25 mm; Chrompack), DANI HT-86.10 gas chromatograph; tR in min; acetate 13: temp. program 608 (3 min)
À58/min À1808 (2min); tR 9.02(( R)-13), 9.32(( S)-13), acetate 12: temp. program 508 (3 min) 88/min 1008
(30 min) 88/min 1808 (1 min); tR 10.58 ((R)-12), 10.68 ((S)-12); 23: temp. program 508 (3 min) 48/min
1608 88/min 1808 (5 min); tR 21.70 ((S)-23), 22.17 ((R)-23). TLC: Merck silica gel 60 F254 plates. Column
chromatography (CC): silica gel. Optical rotations: Dr. Kernchen-Propol digital automatic polarimeter.
Microanalyses: Analyzer 1106 Carlo-Erba. 1H- and 13C-NMR: Bruker AC-250 spectrometer (250 MHz 1H);
CDCl3 solns. at r.t. unless otherwise stated, chemical shifts d in ppm rel. to internal SiMe4, J values in Hz. GC-
MS: HP-6890 gas-chromatograph, 5973 mass detector, HP-5MS column (30 m  0.25 mm  0.25 mm), temp.
program 608(1 min) 68/min 1508 (1 min) 128/min 2808 (5 min); tR in min.
1. Lipase-Mediated Acetylation. 1.1. General Procedure 1 (GP1). A mixture of the suitable substrate (10 g),
lipase (7 g), and vinyl acetate (10 ml) in tBuOMe (80 ml) was stirred at r.t. for 24 h. The residue obtained upon
evaporation of the filtered mixture was submitted to CC.
1.2. (4S)-4-Acetoxyheptan-2-one ((S)-13). According to GP1 (5 day reaction time), with racemic 4 (130 g,
1 mol) and CCL. CC (hexane/AcOEt 9 :1) gave (S)-13 (30.9 g, 18%). Chemical purity 96% by GC/MS (tR
10.41); 60% ee (chiral GC). [a]2D0 ˆ À0.71 (c ˆ 1.12, CHCl3). 1H-NMR: 5.25 (quint., J ˆ 6.7, HÀC(4)); 2.6 2.9
(m, 2 HÀC(3)); 2.13 (s, Me(1)); 2.0 (s, MeCOO); 1.20 1.55 (m, CH2CH2); 0.88 (t, J ˆ 7.1, MeCH2). 13C-NMR:
‡
205.6; 170.4; 70.1; 50.3; 46.8; 30.1; 23.1; 21.5; 20.8. GC/MS: 129 (7, [M À 43] ), 112(17), 97 (21), 43 (100). Anal.
calc. for C9H16O3: C 62.77, H 9.36; found: C 62.38, H 9.58.
1.3. (4S)-4-Acetoxy-6-methylheptan-2-one ((S)-12) and (4R)-4-Hydroxy-6-methylheptan-2-one ((R)-5).
According to GP1 (5 day reaction time), with racemic 5 (60.0 g, 0.42mol) and lipase PS. CC (hexane/AcOEt
9 :1) gave (S)-12 (23.3 g, 30%). Chemical purity 97% by GC/MS (tR 11.36); 95% ee (chiral GC). [a]2D0 ˆ À21.8
1
(c ˆ 1.02, CHCl3). H-NMR [27]: 5.10 5.40 (m, HÀC(4)); 2.72 (dd, J ˆ 7.3, 16.2, HÀC(3)); 2.59 (dd, J ˆ 5.6,
16.2, 1 HÀC(3)); 2.16 (s, Me(1)); 2.02 (s, MeCOO); 1.72 1.24 ( m, CH2CH); 0.93 0.92(2 d, J ˆ 6.7, Me2CH).
‡
13C-NMR: 208.1; 170.8; 68.7; 50.4; 45.7; 31.0; 24.2; 23.2; 21.8; 20.8. GC/MS: 171 (0.5, [M À 15] ), 143 (6), 126
(7), 108 (20), 43 (100).
The unreacted 5, recovered by CC, was enantiomerically enriched by prolonged (15 days) lipase-PS
treatment, according to GP1. CC (hexane/AcOEt 95 :5) gave (R)-5 (21.2 g, 35%). Chemical purity 97% by GC/
MS (tR 8.11); 91% ee (chiral GC of the corresponding acetate). [a]2D0 ˆ À46.6 (c ˆ 0.97, CHCl3) ([12]: (S)-5
[a]D ˆ ‡47.04 (c ˆ 0.7, CHCl3; 84% ee). 1H-NMR [12]: 4.20 4.05 (m, HÀC(4)); 2.70 2.40 (m, 2 HÀC(3));
2.18 (s, Me(1)); 1.80 1.70 (m, HÀC(6)); 1.55 1.40 (m, 1 HÀC(5)); 1.20 1.05 (m, HÀC(5)); 0.92( d, J ˆ 6.4,
‡
2 Me2CH). 13C-NMR: 210.0; 65.6; 50.3; 45.4; 30.8; 24.3; 23.2; 21.9. GC/MS: 143 (0.5 [M À 1] ), 126 (3), 108
(18), 43 (100).
1.4. (2R,3E)-4-Phenylpent-3-en-2-ol Acetate ((R,E)-23) and (2S,3E)-4-Phenylpent-3-en-2-ol ((S,E)-22).
According to GP1 (48 h reaction time), with racemic (E)-22 (60.0 g, 0.37 mol) and lipase PS. CC (hexane/
AcOEt 9 :1) gave (R,E)-23 (27.2 g, 36%) and (S,E)-22 (22.1 g, 37%).
Data of (R,E)-23: Chemical purity 98% by GC/MS (tR 17.51); > 99% ee (chiral GC). [a]2D0 ˆ ‡68.5 (c ˆ
1.01, CHCl3). 1H-NMR [28]: 7.50 7.20 (m, 5 arom. H); 5.80 5.60 (m, HÀC(3), HÀC(2)); 2.1 (s, Me(5)); 2.03
(s, MeCOO); 1.41 (d, J ˆ 6.2, Me(1)). 13C-NMR: 170.5; 142.5; 137.9; 133.1; 128.2; 127.4; 125.8; 68.3; 21.3; 20.8;
‡
16.2. GC/MS: 204 (11, M ), 161 (33), 129 (100).
Data of (S,E)-22. Chemical purity 96% by GC/MS (tR 15.06); > 99% ee (chiral GC of the corresponding
acetate). [a]2D0 ˆ À44.3 (c ˆ 1.0, CHCl3). 1H-NMR [16]: 7.49 7.21 (m, 5 arom. H); 5.80 (dq, J ˆ 8.5, 1.5,
HÀC(3)); 4.76 (dq, J ˆ 8.5, 6.2, HÀC(2)); 2.1 (s, Me(5)); 1.35 (d, J ˆ 6.2, Me(1)). 13C-NMR: 142.9; 136.0; 131.8;
‡
128.1; 127.2; 125.5; 65.0; 23.5; 16.0. GC/MS: 162 (27, M ), 147 (100), 129 (73).
1.5. (3RS,5S)-3-Methyloctane-1,3,5-triol 1-Acetate ((3RS,5S)-19). According to GP1 (24 h reaction time),
with (3RS,5S)-16b (5.70 g, 0.032mol; 1.8 :1 diastereoisomer mixture) and lipase PS. CC (hexane/AcOEt 9 :1)
gave (3RS,5S)-19 (5.44 g, 78%; 2:1 diastereoisomer mixture): 1H-NMR: 4.24 (m, CH2OAc of both diast.);
3.90 4.10 (m, CHOH of both diast.); 2.10 1.32 (m, 8 H of both diast.); 1.26 (s, MeÀC(3) of one diast.); 1.25 (s,
4
)
For other approaches to racemic 22, see [25].

Helvetica Chimica Acta Vol. 87 (2004)
775
MeÀC(3) of the other diast.); 0.81 0.98 (m, 2 MeCH of both diast.). GC/MS: diast. I (tR 18.72): 175 (1, [M À
‡
‡
43] ), 157 (11), 131 (36), 97 (40), 71 (100); diast. II (tR 18.88) 175 (1, [M À 43] ), 157 (15), 131 (38), 97 (42), 71
(100). Anal. calc. for C11H22O4: C 60.52, H 10.16; found: C 60.74, H 10.55.
1.6. (2R,4R)-2-Methyl-2-phenylpentan-1,4-diol 4-Acetate ((2R,4R)-28) and (2R,4R)-2-Methyl-2-phenyl-
pentan-1,4-diol 1-Acetate ((2R,4R)-27). According to GP1 (5 day reaction time), with (2R,4R)-26 (2.70 g,
0.014 mol) and lipase PS. CC (hexane/AcOEt 9 :1) gave (2R,4R)-28 (1.06 g, 32%) and (2R,4R)-27 (1.15 g, 35%).
Data of (2R,4R)-28: Chemical purity 92% by GC/MS (tR 20.89 min) with 8% of (2R,4R)-27 by GC/MS (tR
20.65 min). [a]D20 ˆ À8.97 (c ˆ 0.86, CHCl3). 1H-NMR: 7.49 7.11 (m, 5 arom. H); 4.90 5.00 (m, CHOAc); 3.72
(d, J ˆ 11.2, 1 H, CH2OH); 3.59 (d, J ˆ 11.2, 1 H, CH2OH); 1.93 (s, MeCOO); 1.96 1.83 (m, 2 HÀC(3)); 1.38 (s,
Me(5)); 1.07 (d, J ˆ 7.0, MeCH). 13C-NMR: 148.3; 128.7; 126.5; 126.4; 125.7; 72.1; 65.1; 48.9; 42.6: 25.6; 21.5;
‡
20.7. GC/MS: 175 (1, [M À 61] ), 161 (2), 145 (100). Anal. calc. for C14H20O3: C 71.16, H 8.53; found: C 71.39,
H 8.88.
Data of (2R,4R)-27: Chemical purity 83% by GC/MS (tR 20.65 min) with 17% of (2R,4R)-28 by GC/MS (tR
20.89 min). [a]D20 ˆ À5.94 (c ˆ 0.98, CHCl3). 1H-NMR: 7.39 7.18 (m, 5 arom. H); 4.27 (d, J ˆ 11.2, 1 H,
CH2OAc); 4.19 (d, J ˆ 11.2, 1 H, CH2OAc); 3.80 3.75 (m, CHOH); 2.01 (s, MeCOO); 1.95 1.85 (m,
2 HÀC(3)); 1.49 (s, Me(5)); 1.07 (d, J ˆ 7.0, MeCH). 13C-NMR: 148.2; 128.5; 126.4; 126.0; 125.8; 70.7; 66.2; 48.8;
‡
42.5; 25.6; 21.5; 20.7. GC/MS: 176 (1, [M À 60] ), 163 (6), 119 (100). Anal. calc. for C14H20O3: C 71.16, H 8.53;
found: C 70.87, H 8.21.
1.7. (2S,4S)-2-Methyl-2-phenylpentan-1,4-diol 1-Acetate ((2S,4S)-27). According to GP1 (5 day reaction
time), with (2S,4S)-26 (2.70 g, 0.014 mol) and lipase PS. CC (hexane/AcOEt 9 :1) gave (2S,4S)-27 (1.44 g, 44%).
Chemical purity 92% by GC/MS (tR 20.65 min) with 8% of (2S,4S)-28 by GC/MS (tR ˆ 20.89 min). [a]2D0 ˆ ‡21.3
(c ˆ 0.77, CHCl3). 1H-NMR and GC/MS: in accordance with those of the enantiomer. Anal. calc. for C14H20O3:
C 71.16, H 8.53; found: C 71.47, H 8.76.
1.8. (4S)-4-Hydroxyheptan-2-one ((S)-4). Saponification of (S)-13 (30.9 g, 0.18 mol) in H2O/THF 9 :1 at
pH 7.8 (pH-stat) in the presence of CCL gave, after CC (hexane/AcOEt 8 :2), (S)-4 (15.7 g, 67%). Chemical
purity 95% by GC/MS (tR 6.82); 80% ee (chiral GC of the corresponding acetate). [a]2D0 ˆ ‡45.2( c ˆ 0.965,
CHCl3) ([10]: [a]D ˆ ‡35.1 (c ˆ 2.1 CHCl3; 58% ee); [12]: [a]D ˆ ‡ 42.3 (c ˆ 5, CHCl3; 84% ee); [17]: [a]D
ˆ
‡44 (c ˆ 0.18, CHCl3; 73% ee)). 1H-NMR [29]: 4.00 (m, HÀC(4)); 2.55 (m, 2 HÀC(3)); 2.13 (s, MeCO); 1.20
1.55 (m, CH2CH2); 0.90 (t, J ˆ 7.1, MeCH2). 1.36 (d, J ˆ 6.4, Me). 13C-NMR: 205.7; 67.4; 50.2; 46.9; 30.2; 23.3;
‡
21.7. GC/MS: 129 (1, [M À 1] ), 112 (12), 97 (18), 87 (62), 43 (100).
2. Addition of Allylmagnesium Bromide to Hydroxy or Acetoxy Ketone Derivatives. 2.1. General Procedure
2 (GP2). The suitable hydroxy or acetoxy derivative (0.10 mol) was dropped into a soln. of allylmagnesium
bromide (from 0.3 or 0.4 mol of allyl bromide and 0.33 or 0.44 mol of Mg) in Et2O (500 ml) at 108. The mixture
was refluxed for 1 h, poured into ice, quenched with sat. NH4Cl soln., and extracted with Et2O. The org. phase
was dried (Na2SO4) and evaporated and the residue submitted to CC (hexane/AcOEt 7:3).
2.2. (4RS,6S)-4-Methylnon-1-ene-4,6-diol ((4RS,6S)-14a). According to GP2, with (S)-4 (80% ee; 15.5 g,
1
0.12mol): (4 RS,6S)-14a (14.8 g, 72%; 1.8 :1 diastereoisomer mixture (GC/MS)). H-NMR: 6.01 (dd, J ˆ 11.0,
17.3, HÀC(2)); 5.32 (dd, J ˆ 17.3, 1.4, 1 HÀC(1)); 5.05 (dd, J ˆ 11.0, 1.4, 1 HÀC(1)); 4.10 3.90 (m, HÀC(6));
1.90 (d, J ˆ 14.7, 1 HÀC(3)); 1.74 (d, J ˆ 14.7, HÀC(3)); 1.54 1.16 (m, 3 CH2, Me); 0.93 (t, J ˆ 7.1, Me(9)). GC/
‡
‡
MS: diast. I (tR 12.16): 157 (5, [M À 15] ), 131 (44), 113 (100), 93 (66); diast. II (tR 12.27) 157 (5, [M À 15] ), 131
(45), 113 (100), 93 (55). Anal. calc. for C10H20O2: C 69.72, H 11.70; found: C 69.41, H 11.57.
2.3. (4RS,6R)-4,8-Dimethylnon-1-ene-4,6-diol ((4RS,6R)-15a). According to GP2, with (R)-5 (91% ee;
21.0 g, 0.15 mol): (4RS,6R)-15a 1.9 :1 diastereoisomer mixture (GC/MS). 1H-NMR: 5.72 6.00 ( m, HÀC(2) of
both diast.); 5.21 5.05 (m, 2 HÀC(1) of both diast.); 4.15 4.0 (m, HÀC(6) of both diast.); 2.49 2.20 (m,
2 HÀC(3) of both diast.); 1.90 1.65 (m, HÀC(8) of both diast.); 1.61 1.1 (m, 2 HÀC(5), 2H ÀC(7) of both
diast.); 1.29 (s, MeÀC(4) of one diast.); 1.21 (s, MeÀC(4) of the other diast.); 0.99 0.87 (m, 2 MeCH of both
‡
diast.). GC/MS: diast. I (tR 13.11) 171 (2, [M À 15] ), 145 (20), 109 (65), 43 (100); diast. II (tR 13.26); 171 (2,
‡
[M À 15] ), 145 (17), 109 (73), 43 (100). Anal. calc. for C11H22O2: C 70.92, H 11.90; found: C 70.38, H 11.57.
2.4. (4RS,6S)-4,8-Dimethylnon-1-ene-4,6-diol ((4RS,6S)-15a). According to GP2, with (S)-12 (95% ee;
23.0 g, 0.12 mol): (4RS,6S)-15a (16.3 g, 71%; 1.9 :1 diastereoisomer mixture (GC/MS)). 1H-NMR and GC/MS:
in accordance with those of (4RS,6R)-15a. Anal. calc. for C11H22O2: C 70.92, H 11.90; found: C 71.13, H 12.21.
3. Ozonolysis of Diols 14a and 15a. 3.1. General Procedure 3 (GP3). The suitable diol derivative (0.12mol)
was acetylated with Ac2O (20 ml) in pyridine (20 ml). The resulting monoacetate was treated with O3 at À788 in
CH2Cl2/MeOH 1:1 (400 ml). The mixture was quenched with NaBH4 (0.24 mol, 9.12 g). After the usual
workup, the residue was submitted to CC (hexane/AcOEt 8 :2).

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Helvetica Chimica Acta Vol. 87 (2004)
3.2. (3RS,5S)-3-Methyloctane-1,3,5-triol 5-Acetate ((3RS,5S)-16a). According to GP3, with (4RS,6S)-14a
(14.5 g, 0.084 mol): (3RS,5S)-16a (13.4 g, 73%; 1:2diastereoisomer mixture (GC/MS)). 1H-NMR: 5.30 5.10
(m, CHOAc); 3.90 3.70 (m, CH2OH); 2.05 (s, MeCOO); 1.8 1.3 (m, 8 H); 1.2 5 (s, MeÀC(4)); 0.95 (t, J ˆ 7.0,
‡
MeCH2). GC/MS: diast. I (tR 18.57) 173 (1, [M À 45] ), 143 (13), 113 (58), 89 (76), 43 (100); diast. II (tR 18.75)
‡
173 (4, [M À 45] ), 143 (11), 113 (59), 89 (78), 43 (100). Anal. calc. for C11H22O4: C 60.52, H 10.16; found:
C 60.38, H 10.42.
3.3. (3RS,5R)-3,7-Dimethyloctane-1,3,5-triol 5-Acetate ((3RS,5R)-17a). According to GP3, with (4RS,6R)-
1
15a (20.3 g, 0.11 mol): (3RS,5R)-17a (17.4 g, 69%; 1:1.8 diastereoisomer mixture (GC/MS)). H-NMR: 5.23
5.05 (m, CHOAc of one diast.); 4.28 4.18 (m, CH2OH of one diast.); 4.17 4.02( m, CHOAc of one diast.);
3.75 3.95 (m, CH2OH of one diast.); 2.06 (s, AcO of one diast.); 2.04 (s, AcO of one diast.); 2.00 1.12 (m, 10 H
‡
of both diast.); 0.97 0.88 (m, 2 MeCH of both diast.). GC/MS: diast. I (tR 19.10) 187 (5, [M À 45] ), 157 (13),
‡
127 (35), 89 (95), 43 (100); diast. II (tR 19.28) 187 (5, [M À 45] ), 157 (11), 127 (33), 89 (100), 43 (95). Anal.
calc. for C12H24O4: C 62.04, H 10.41; found: C 62.35, H 10.73.
3.4. (3RS,5S)-3,7-Dimethyloctane-1,3,5-triol 5-Acetate ((3RS,5S)-17a). According to GP3, with (4RS,6S)-
15a (16.0 g, 0.086 mol): (3RS,5S)-17a (14.9 g, 75%; 1:1.8 diastereoisomer mixture (GC/MS)). 1H-NMR and
GC/MS: in accordance with those described for (3RS,5R)-17a. Anal. calc. for C12H24O4: C 62.04, H 10.41; found:
C 61.89, H 10.11.
4. Saponifications: 16b and 17b. 4.1. (3RS,5S)-3-Methyloctane-1,3,5-triol ((3RS,5S)-16b). Saponification of
(3RS,5S)-16a (13.4 g, 0.061 mol) with KOH (4.47 g, 0.080 mol) in MeOH (100 ml) gave (3RS,5S)-16b (9.56 g,
89%; 1.8 :1 diastereoisomers mixture). 1H-NMR: 4.10 4.00 (m, CHOH); 3.90 3.80 (m, CH2OH); 1.7 1.3 (m,
‡
8 H); 1.2 7 (s, MeÀC(3)); 0.95 (t, J ˆ 7.0, MeCH2). GC/MS: diast. I (tR 17.19): 161 (1, [M À 15] ), 131 (24), 113
‡
(39), 89 (67), 43 (100); diast. II (tR 17.27) 161 (4, [M À 45] ), 131 (20), 113 (40), 89 (70), 43 (100). Anal. calc. for
C9H20O3: C 61.33, H 11.44; found: C 61.75., H 11.69.
4.2. (3RS,5R)-3,7-Dimethyloctane-1,3,5-triol ((3RS,5R)-17b). Saponification of (3RS,5R)-17a (17.1 g,
0.074 mol) with KOH (5.39 g, 0.096 mol) in MeOH (100 ml) gave (3RS,5R)-17b (12.7 g, 91%; diastereoisomer
1
mixture). H-NMR: 4.24 3.80 (m, CH2OH, CHOH of both diast.); 2.22 (ddd, J ˆ 5.0, 10.8, 15.1, 1 H of one
diast.); 1.88 1.09 (m, 6 H of both diast., and 1 H of one diast.; 1.35 (s, MeÀC(3) of one diast.); 1.31 (s, MeÀC(3)
of the other diast.); 0.86 0.99 (m, 2 MeCH of both diast.). GC/MS: br. single peak (tR 18.25): 145 (23, [M À
‡
45] ), 115 (31), 109 (51), 89 (86), 43 (100). Anal. calc. for C10H22O3: C 63.12, H 11.65; found: C 63.44., H 11.32.
4.3. (3RS,5S)-3,7-Dimethyloctane-1,3,5-triol ((3RS,5S)-17b). Saponification of (3RS,5S)-17a (14.9 g,
0.064 mol) with KOH (4.67 g, 0.083 mol) in MeOH (100 ml) gave (3RS,5S)-17b (11.4 g, 94%; diasteroisomer
mixture). 1H-NMR and GC/MS: in accordance with those of (3RS,5R)-17b. Anal. calc. for C10H22O3: C 63.12,
H 11.65; found: C 63.44, H 11.32.
5. Pyranols 18 and 2. 5.1. (2S,4R)- and (2S,4S)-Tetrahydro-4-methyl-2-propyl-2H-pyran-4-ol ((2S,4R)- and
(2S,4S)-18) [30]. Treatment of (3RS,5S)-16b (3.7 g, 0.021 mol) with TsCl (5.99 g, 0.031 mol) in pyridine (20 ml)
gave, after CC (hexane/AcOEt 95 :5), (2S,4R)-18 (1.29 g, 39%) and (2S,4S)-18 (1.03 g, 31%).
Data of (2S,4R)-18: Chemical purity 96% by GC/MS (tR 9.27); > 99% de (GC/MS). [a]2D0 ˆ ‡0.83 (c ˆ 0.97,
1
CHCl3). H-NMR: 3.90 3.80 (m, 1 H); 3.79 3.65 (m, 1 H); 3.65 3.45 (m,1 H); 1.75 1.18 (m, 8 H); 1.2 6 (s,
‡
MeÀC(4)); 0.92( t, J ˆ 7.0, MeCH2). GC/MS: 157 (1, [M À 1] ), 140 (37), 115 (44), 71 (100), 43 (90).
Data of (2S,4S)-18: Chemical purity 97% by GC/MS (tR 9.71); > 99% de. [a]2D0 ˆ ‡5.32( c ˆ 1.01, CHCl3).
1H-NMR: 3.96 (ddd, J ˆ 12.0, 5.2, 1.8, HeqÀC(6)); 3.43 (dt, J ˆ 2.6, 12.0, HaxÀC(6)); 3.40 3.20 (m, HaxÀC(2));
‡
1.83 1.14 (m, 8 H); 1.33 (s, MeÀC(4)); 0.91 (t, J ˆ 7.1, MeCH2). GC/MS: 157 (1, [M À 1] ), 140 (8), 115 (69), 71
(100), 43 (91).
5.2. (2R,4S)- and (2R,4R)-Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol ((2R,4S)- and (2R,4R)-
2, resp. As described in 5.1, with (3RS,5R)-17b (12.6 g, 0.066 mol), TsCl (18.81 g, 0.099 mol), and pyridine
(20 ml): (2R,4S)-2 (4.2g, 37%) and (2 R,4R)-2 (3.4 g, 30%).
Data of (2R,4S)-2: Chemical purity 98% by GC/MS (tR 10.47); 96% de (GC/MS); 91% ee (from (R)-5).
[a]2D0 ˆ À0.98 (c ˆ 1.27, CHCl3). 1H-NMR (400 MHz): 3.80 (ddd, J ˆ 11.5, 5.5, 1.8, HeqÀC(6)); 3.73 (ddd, J ˆ
12.5, 11.5, 2.4, HaxÀC(6)); 3.66 (dddd, J ˆ 11.1, 8.4, 4.4, 2.2, HÀC(2)); 1.82 1.70 (m, Me2CH); 1.63 (ddd, J ˆ
13.6, 12.5, 5.5, HaxÀC(5)); 1.50 (dt, J ˆ 13.6, 2.4, HeqÀC(3)); 1.44 1.38 (m, HeqÀC(5), 1 H Me2CHCH2); 1.27
(dd, J ˆ 13.6, 11.1, HaxÀC(3)); 1.23 (s, MeÀC(4)); 1.11 (ddd, J ˆ 13.3, 8.3, 4.5, 1 H Me2CHCH2); 0.88 (d, J ˆ 6.6,
‡
Me2CH). 13C-NMR: 71.1; 67.9; 63.5; 45.3; 45.1; 38.7; 31.7; 24.2; 23.2; 22.2. GC/MS: 172 (1, M ), 154 (25), 139
(20), 115 (58), 69 (100), 43 (75).
Data of (2R,4R)-2: Chemical purity 97% by GC/MS (tR 10.81); > 99% de (GC/MS); 91% ee (from (R)-5).
[a]2D0 ˆ À4.5 (c ˆ 1.83, CHCl3). 1H-NMR (400 MHz): 3.95 (ddd, J ˆ 12.0, 5.4, 2.0, HeqÀC(6)); 3.41 (ddd, J ˆ 12.5,

Helvetica Chimica Acta Vol. 87 (2004)
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11.9, 2.4, HaxÀC(6)); 3.34 (ddd, J ˆ 11.2, 8.2, 4.4, 2.3, HaxÀC(2)); 1.82 1.72 ( m, Me2CH); 1.69 (dddq, J ˆ 12.7,
12.5, 5.4, 0.8, HaxÀC(5)); 1.62( dt, J ˆ 12.5, 2.4, HeqÀC(3)); 1.58 (dddd, J ˆ 12.6, 2.4, 2.3, 2.0, HeqÀC(5)); 1.49
(ddd, J ˆ 13.9, 8.3, 5.9, 1 H, Me2CHCH2); 1.35 (ddq, J ˆ 12.5, 11.5, 0.8, HaxÀC(3)); 1.32( t, J ˆ 0.8, MeÀC(4));
1.17 (ddd, J ˆ 13.9, 8.3, 4.5, 1 H, Me2CHCH2), 0.88 (d, J ˆ 6.6, 2 Me2CH). 13C-NMR: 73.5; 68.7; 65.3; 46.9; 45.3;
‡
40.6; 25.3; 24.2; 23.1; 22.3. GC/MS: 154 (10, [M À 18] ), 139 (8), 115 (85), 71 (100), 43 (80).
5.3. (2S,4R)- and (2S,4S)-Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol ((2S,4R)- and (2S,4S)-2,
resp.). As described in 5.1, with (3RS,5S)-17b (11.2g, 0.059 mol), TsCl (16.72g, 0.088 mol), and pyridine
(20 ml): (2S,4R)-2 (3.55 g, 35%) and (2S,4S)-2 (2.94 g, 29%).
Data of (2S,4R)-2: Chemical purity 98% by GC/MS (tR 10.47); > 99% de (GC/MS); 95% ee (from (S)-12).
1
[a]2D0 ˆ ‡1.22 (c ˆ 1.63, CHCl3). H-NMR and GC/MS: in accordance with those of the enantiomer.
Data of (2S,4S)-2: Chemical purity 97% by GC/MS (tR 10.81); > 99% de (GC/MS); 95% ee (from (S)-12).
[a]2D0 ˆ ‡4.9 (c ˆ 1.14, CHCl3). 1H-NMR and GC/MS: in accordance with those of the enantiomer.
5.4. (2R,4S)- and (2R,4R)-Tetrahydro-4-methyl-2-propyl-2H-pyran-4-ol ((2R,4S)- and (2R,4R)-18, resp.).
The mixture (3RS,5S)-19 (5.30 g, 0.024 mol) was treated with TsCl (6.93 g, 0.036 mol) in pyridine (30 ml). After
the usual workup, saponification with 10% NaOH soln. (10 ml) in EtOH (50 ml) gave, after CC (hexane/AcOEt
95 :5), (2R,4R)-18 (1.29 g, 34%) and (2R,4S)-18 (1.14 g, 30%).
Data of (2R,4S)-18: Chemical purity 95% by GC/MS (tR 9.27); > 99% de (GC/MS). [a]2D0 ˆ À0.63 (c ˆ
1
0.96, CHCl3). H-NMR and GC/MS: in accordance with those of the enantiomer.
Data of (2R,4R)-18: Chemical purity 96% by GC/MS (tR 9.71); > 99% de. [a]2D0 ˆ À4.40 (c ˆ 1.0, CHCl3).
1H-NMR and GC/MS: in accordance with those of the enantiomer.
6. Pyranol Acetates 1. 6.1. (2S,4R)-Tetrahydro-4-methyl-2-propyl-2H-pyran-4-ol Acetate ((2S,4R)-1).
Treatment of (2S,4R)-18 (1.10 g, 6.96 mmol) in refluxing Ac2O (10 ml) in the presence of NaOAc (0.856 g,
10.4 mmol) gave, after the usual workup, (2S,4R)-1 (1.06 g, 76%): Chemical purity 95% by GC/MS (tR 12.06);
1
> 99% de (GC/MS); 80% ee (from (S)-4). [a]D20 ˆ À3.11 (c ˆ 0.94, CHCl3). H-NMR (400 MHz, C6D6): 3.71
(ddd, J ˆ 11.6, 5.3, 1.6, HeqÀC(6)); 3.57 (ddd, J ˆ 12.6, 11.6, 2.1, HaxÀC(6)); 3.52( dddd, J ˆ 11.4, 7.4, 4.6, 2.3,
HaxÀC(2)); 2.20 (dt, J ˆ 13.8, 2.3, HeqÀC(3)); 2.05 (dddd, J ˆ 14.1, 2.3, 2.1, 1.6, HeqÀC(5)); 1.68 (s, MeCOO),
1.40 (s, MeÀC(4)); 1.60 1.25 (m, CH2CH2); 1.28 (ddd, J ˆ 14.1, 12.6, 5.3, HaxÀC(5)); 1.02( dd, J ˆ 13.8, 11.3,
‡
HaxÀC(3)); 0.89 (t, J ˆ 7.2, MeCH2). GC/MS: 157 (0.5, [M À 43] ), 140 (20), 125 (30), 97 (100).
6.2. (2S,4S)-Tetrahydro-4-methyl-2-propyl-2H-pyran-4-ol Aacetate ((2S,4S)-1). As described in 6.1, with
(2S,4S)-18 (0.95 g, 6.01 mmol), Ac2O (10 ml), and NaOAc (0.739 g, 9.02mmol): (2 S,4S)-1 (0.889 g, 74%).
Chemical purity 95% by GC/MS (tR 13.24); > 99% de (GC/MS); 80% ee (from (S)-4). [a]2D0 ˆ À1.67 (c ˆ 0.94,
CHCl3). 1H-NMR (400 MHz): 3.93 (ddd, J ˆ 12.1, 5.3, 1.9, HeqÀC(6)); 3.46 (ddd, J ˆ 12.6, 12.1, 2.3, HaxÀC(6));
3.33 (m, HaxÀC(2)); 2.10 (dt, J ˆ 12.6, 2.2, HeqÀC(3)); 2.03 (dddd, J ˆ 12.8, 2.3, 2.2, 1.9, HeqÀC(5)); 1.97 (s,
MeCOO), 1.86 (dddq, J ˆ 12.8, 12.6, 5.3, 0.9, HaxÀC(5)); 1.62( t, J ˆ 0.9, MeÀC(4)); 1.55 1.30 (m, CH2CH2);
‡
1.54 (ddq, J ˆ 12.6, 11.5, 0.9, HaxÀC(3)); 0.91 (t, J ˆ 7.2, MeCH2). GC/MS: 157 (0.5, [M À 43] ), 140 (20), 125
(30), 97 (100).
6.3. (2R,4S)-Tetrahydro-4-methyl-2-propyl-2H-pyran-4-ol Acetate ((2R,4S)-1).
As described in 6.1, with (2R,4S)-18 (1.00 g, 6.32mmol), Ac 2O (10 ml), and NaOAc (0.777 g, 9.48 mmol):
(2R,4S)-1 (0.872g, 69%). Chemical purity 97% by GC/MS ( tR 12.06); > 99% de (GC/MS). [a]2D0 ˆ ‡3.8 (c ˆ
1
0.94, CHCl3). H-NMR and GC/MS: in accordance with those of the enantiomer.
6.4. (2R,4R)-Tetrahydro-4-methyl-2-propyl-2H-pyran-4-ol Acetate ((2R,4R)-1). As described in 6.1, with
(2R,4R)-18 (1.00 g, 6.32mmol), Ac 2O (10 ml), and NaOAc (0.777 g, 9.48 mmol): (2R,4R)-1 (0.808 g, 64%).
Chemical purity 94% by GC/MS (tR 13.24); > 99% de (GC/MS). [a]2D0 ˆ ‡1.88 (c ˆ 0.96, CHCl3). 1H-NMR and
GC/MS: in accordance with those of the enantiomer.
7. Rhubafurans 3. 7.1. Precursors 22 26. (2R,3E)-4-Phenylpent-3-en-2-ol ((R,E)-22). Saponification of
(R,E)-23 (27.0 g, 0.132mol) with KOH (9.63 g, 0.172mol) in MeOH (300 ml) gave, after the usual workup, ( R)-
22 (19.7 g, 92%). [a]2D0 ˆ ‡45.8 (c ˆ 1.1, CHCl3). 1H-NMR and GC/MS: in accordance with those of the
enantiomer.
(3R,4E)-3-Methyl-3-phenylhex-4-enoic Acid ((R,E)-24). A soln. of (R,E)-22 (19.4 g, 0.12mol) in triethyl
orthoacetate (500 ml), in the presence of propanoic acid (0.5 ml) was heated at 1408, removing EtOH by
distillation. After evaporation, the residue was treated with 10% NaOH soln. (50 ml) in refluxing EtOH
(200 ml). The mixture was poured into H2O, acidified with 10% HCl soln., and extracted with Et2O. The org.
phase was dried (Na2SO4) and evaporated: (R,E)-24 (15.6 g, 64%): [a]2D0 ˆ ‡2.88 (c ˆ 1.04, CHCl3); 1H-NMR:
7.36 7.13 (m, 5 arom. H); 5.76 (dq, J ˆ 15.7, 1.7, HÀC(4)); 5.47 (dq, J ˆ 15.7, 6.1, HÀC(5)); 2.81 (d, J ˆ 14.5, 1
HÀC(2)); 2.75 (d, J ˆ 14.5, 1 HÀC(2)); 1.72 (dd, J ˆ 1.7, 6.1, Me(6)); 1.53 (s, MeÀC(3)). 13C-NMR: 177.4; 146.4;

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Helvetica Chimica Acta Vol. 87 (2004)
138.1; 128.1; 126.2; 126.0; 123.1; 45.8; 42.4; 26.1; 18.1. Anal. calc. for C13H16O2: C 76.44, H 7.90; found: C 76.73,
H 7.58.
(3S,4E)-3-Methyl-3-phenylhex-4-enoic Acid ((S,E)-24). As described for (R,E)-24, with (S,E)-22 (22.0 g,
0.13 mol): (S,E)-24 (16.62g, 60%). [ a]2D0 ˆ À2.67 (c ˆ 0.94, CHCl3). 1H-NMR and GC/MS: in accordance with
those of the enantiomer. Anal. calc. for C13H16O2: C 76.44, H 7.90; found: C 76.12, H 7.08.
(4R,5E)-4-Methyl-4-phenylhept-5-en-2-one ((R,E)-25). A soln. of (R,E)-24 (15.5 g, 0.076 mol) in THF
(100 ml) was treated with ethyl carbonochloridate (9.82g, 0.091 mol) and Et 3N (9.19 g, 0.091 mol) at 08. The
mixture was poured into H2O and extracted with Et2O, the org. phase dried (Na2SO4) and evaporated, and the
residue dissolved in THF (150 ml). To this soln., 3m MeMgCl (33 ml, 0.099 mol) was quickly added at À208. The
mixture was poured into sat. NH4Cl soln. and extracted with Et2O, the org. phase evaporated, and the residue
submitted to CC (hexane): (R,E)-25 (10.59 g, 69%). Chemical purity 97% by GC/MS (tR 17.52). [a]2D0 ˆ À11.06
(c ˆ 0.95, CHCl3). 1H-NMR: 7.36 7.15 (m, 5 arom. H); 5.76 (dq, J ˆ 15.7, 1.5, HÀC(5)); 5.47 (dq, J ˆ 15.7, 6.6,
HÀC(6)); 2.92 (d, J ˆ 14.3, 1 HÀC(3)); 2.82 (d, J ˆ 14.3, 1 HÀC(3)); 1.87 (s, MeCO); 1.73 (dd, J ˆ 1.5, 6.6,
Me(7)); 1.48 (s, MeÀC(4)). 13C-NMR: 208.1; 146.9; 138.8; 138.1; 128.1; 126.3; 122.7; 29.7; 26.11; 18.1; GC/MS:
‡
187 (3, [M À 15] ), 159 (12), 145 (100), 117 (42). Anal. calc. for C14H18O: C 83.12, H 8.97; found: C 83.47,
H 9.32.
(4S,5E)-4-Methyl-4-phenylhept-5-en-2-one ((S,E)-25). As described for (R,E)-25, with (S,E)-24 (16.5 g,
0.081 mol): (S,E)-25 (10.96 g, 67%). Chemical purity 96% by GC/MS (tR 17.52). [a]2D0 ˆ‡ 10.7 (c ˆ 1.05, CHCl3).
1H-NMR and GC/MS: in accordance with those of the enantiomer. Anal. calc. for C14H18O: C 83.12, H 8.97;
found: C 82.88, H 9.24.
(2S,4R)- and (2S,4S)-2-Methyl-2-phenylpentane-1,4-diol ((2S,4R)- and (2S,4S)-26, resp.). Ketone (R,E)-25
(10.4 g, 0.051 mol) was treated with O3 at À788 in CH2Cl2/MeOH (200 ml). The mixture was quenched with
NaBH4 (3.88 g, 0.102mol). After the usual workup, the residue was separated by CC (hexane/ethyl acetate
7:3): (2S,4R)-26 (3.46 g, 35%) and (2S,4S)-26 (2.87 g, 29%).
Data of (2S,4R)-26: Chemical purity 97% by GC/MS (tR 19.07); > 99% de; > 99% ee (from (R)-23).
[a]2D0 ˆ À8.54 (c ˆ 0.96, CHCl3). 1H-NMR: 7.50 7.12( m, 5 arom. H); 4.00 (d, J ˆ 11.2, HÀC(1)); 3.90 3.77 (m,
HÀC(4)); 3.74 (d, J ˆ 11.2, 1 HÀC(1)); 2.0 1.85 (m, 2 HÀC(3)); 1.28 (s, MeÀC(2)); 1.19 (d, J ˆ 6.2, Me(5)).
‡
13C-NMR: 145.2; 128.4; 128.1; 126.4; 126.1; 69.81; 65.14; 58.2; 48.3; 42.73; 27.4; 25.0; GC/MS: 176 (1, [M À 18] ),
164 (12), 146 (38), 131 (42), 119 (100). Anal. calc. for C12H18O2: C 74.19, H 9.34; found: C 74.35, H 9.01.
Data of (2S,4S)-26: Chemical purity 96% by GC/MS (tR 19.46); > 99% de; > 99% ee (from (R)-23).
[a]2D0 ˆ ‡13.1 (c ˆ 0.89, CHCl3). 1H-NMR: 7.50 7.16 (m, 5 arom. H); 4.1 3.95 (m, HÀC(4)); 3.80 (d, J ˆ 11.2, 1
HÀC(1)); 3.66 (d, J ˆ 11.2, 1 HÀC(1)); 2.01 (dd, J ˆ 9.2, 15.1, 1 HÀC(3)); 1.73 (dd, J ˆ 1.9, 15.1, 1 HÀC(3));
1.41 (s, MeÀC(2)); 1.19 (d, J ˆ 6.2, Me(5)). 13C-NMR: 147.1; 128.3; 126.5; 126.2; 125.8; 70.9; 64.7; 48.9; 42.3;
‡
25.5; 21.5. GC/MS: 176 (1, [M À 18] ), 164 (8), 146 (46), 131 (58), 119 (100). Anal. calc. for C12H18O2: C 74.19,
H 9.34; found: C 73.87, H 9.77.
(2R,4S)- and (2R,4R)-2-Methyl-2-phenylpentane-1,4-diol ((2R,4S)- and (2R,4R)-26, resp.). As described
for (2S,4R)- and (2S,4S)-26, with (S,E)-25 (10.80 g, 0.053 mol), O3, CH2Cl2/MeOH (200 ml), and NaBH4 (4.03 g,
0.106 mol): (2R,4S)-26 (3.19 g, 31%) and (2R,4R)-26 (2.87 g, 28%).
Data of (2R,4S)-26: Chemical purity 96% by GC/MS (tR 19.07); > 99% de; > 99% ee (from (S)-22).
[a]2D0 ˆ ‡8.34 (c ˆ 1.53, CHCl3). 1H-NMR and GC/MS: in accordance with those of the enantiomer. Anal. calc.
for C12H18O2: C 74.19, H 9.34; found: C 74.42., H 9.77.
Data of (2R,4R)-26: Chemical purity 97% by GC/MS (tR 19.46); > 99% de; > 99% ee (from (S)-22).
[a]2D0 ˆ À11.7 (c ˆ 0.87, CHCl3). 1H-NMR and GC/MS: in accordance with those of the enantiomer. Anal. Calc.
For C12H18O2: C 74.19, H 9.34; found: C 74.54, H 8.99.
7.2. Ring Closure of Derivatives 27 and 28. 7.2.1. General Procedure 3 (GP3). The suitable monoacetate
derivative (4.7 mmol) was treated with TsCl (1.34 g, 7.05 mmol) in pyridine (5 ml). After the usual workup,
¾
saponification with 10% NaOH soln. (2ml) in ethanol (10 ml) gave Rhubafuran samples which were purified
by CC (hexane/AcOEt 95 :5).
7.2.2. (2S,4R)-Tetrahydro-2,4-dimethyl-4-phenylfuran ((2S,4R)-3). According to GP3, with (2R,4R)-27
(1.0 g, 4.23 mmol): (2S,4R)-3 (0.417 g, 56%). Chemical purity 97% by GC/MS (tR 13.78); 66% de; > 99% ee
(from (S)-22). [a]2D0 ˆ ‡12.5 (c ˆ 0.97, CHCl3). 1H-NMR (400 MHz): 7.34 7.18 (m, 5 arom. H); 4.12( ddq, J ˆ
7.7, 7.5, 6.2, HÀC(2)); 3.99 (d, J ˆ 12.4, 1 HÀC(5)); 3.91 (d, J ˆ 12.4, 1 HÀC(5)); 2.43 (dd, J ˆ 12.4, 7.5, 1
HÀC(3)); 1.66 (dd, J ˆ 12.4, 7.7, 1 HÀC(3)); 1.45 (s, MeÀC(4)); 1.34 (d, J ˆ 6.2, MeÀC(2)). 13C-NMR: 147.6;
‡
128.3; 125.9; 125.7; 78.9; 75.5; 47.7; 29.1; 28.1; 21.8. GC/MS : 176 (2, M ); 145 (12); 131 (100).
7.2.3. (2R,4R)-Tetrahydro-2,4-dimethyl-4-phenylfuran ((2R,4R)-3). According to GP3, with (2R,4R)-28
(1.0 g, 4.23 mmol): (2R,4R)-3 (0.372g, 50%). Chemical purity 97% by GC/MS ( tR 13.86); 84% de; > 99% ee

Helvetica Chimica Acta Vol. 87 (2004)
779
(from (S)-22). [a]D20 ˆ ‡2.66 (c ˆ 0.67, CHCl3). 1H-NMR: 7.34 7.18 (m, 5 arom. H); 4.32( quint. d, J ˆ 5.9, 9.5,
HÀC(2)); 4.02 (d, J ˆ 8.2, 1 HÀC(5)); 3.90 (d, J ˆ 8.2, 1 HÀC(5)); 2.22 (dd, J ˆ 12.1, 5.9, 1 HÀC(3)); 1.85 (dd,
J ˆ 12.1, 9.5, 1 HÀC(3)); 1.43 (s, MeÀC(4)); 1.29 (d, J ˆ 5.9, MeÀC(2)). 13C-NMR: 147.8; 128.3; 126.0; 125.9;
‡
125.7; 78.5; 74.9; 47.9; 28.1; 21.4. GC/MS: 176 (12, M ); 146 (23), 131 (100).
7.2.4. (2R,4S)-Tetrahydro-2,4-dimethyl-4-phenylfuran ((2R,4S)-3). According to GP3, with (2S,4S)-27
(1.1 g, 4.7 mol): (2R,4S)-3 (0.401 g, 49%). Chemical purity 97% by GC/MS (tR 13.78); 78% de; > 99% ee (from
(R)-23). [a]2D0 ˆ À39.5 (c ˆ 0.4, CHCl3). 1H-NMR and GC/MS: in accordance with those of the enantiomer.
7.2.5. (2S,4S)-Tetrahydro-2,4-dimethyl-4-phenylfuran ((2S,4S)-3). NBS (1.19 g, 6.69 mmol) was added to a
soln. of (2S,4S)-26 (1.0 g, 5.15 mmol) and PPh3 (1.75 g, 6.69 mmol) in CH2Cl2 (20 ml). After 30 min at r.t., the
mixture was poured into H2O and extracted with CH2Cl2. The org. phase was dried (Na2SO4) and evaporated
and the residue submitted to CC (hexane): (2S,4S)-3 (0.607 g, 67%); 60% de, > 99% ee. [a]2D0 ˆ À 10.2( c ˆ
1
0.84, CHCl3). H-NMR and GC/MS: in accordance with those of the enantiomer.
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Received October 20, 2003