Enzyme-mediated preparation of chiral 1,3-dioxane odorants

Article abstract of DOI:10.1002/hlca.200390059

The enantiomerically enriched diastereoisomers of the chiral 1,3-dioxane odorants Floropal (1) and Magnolan (2) were prepared by an enzyme-mediated approach. Their olfactory properties were evaluated to investigate differences in the odor perception for the stereoisomers.

Full text of DOI:10.1002/hlca.200390059

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Helvetica Chimica Acta Vol. 86 (2003)
Enzyme-Mediated Preparation of Chiral 1,3-Dioxane Odorants
by Agnese Abate, Elisabetta Brenna*, Giovanni Fronza, Claudio Fuganti, Sabrina Ronzani, and Stefano Serra
Dipartimento di Chimica, Materiali, Ingegneria Chimica, Politecnico di Milano, ed Istituto CNR per la Chimica
del Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano
¾
The enantiomerically enriched diastereoisomers of the chiral 1,3-dioxane odorants Floropal (1) and
¾
Magnolan (2) were prepared by an enzyme-mediated approach. Their olfactory properties were evaluated to
investigate differences in the odor perception for the stereoisomers.
¾
¾
¾
1. Introduction.
Floropal (or Vertacetal ; 1) and Magnolan (2) are two
structurally correlated dioxane derivatives showing interesting olfactory properties.
Floropal is a grapefruit fragrance with −fruity rhubarb undertones× [1]; Magnolan is a
−substantive floral, rosy odorant× employed to convey the −freshness of rose-flower dew×
in perfume compositions [1]. Floropal and Magnolan are prepared by Prins reaction of
a-methylstyrene and 1H-indene, respectively, with acetaldehyde [2][3], and they are
commercialized as racemic mixtures of the two main diastereoisomers 1a/1b and 2a/2b,
respectively.
O
O
O
O
Ph
1 Floropal® (Vertacetal®)
2 Magnolan®
O
O
O
O
Ph
Ph
1b
1a
O
O
O
O
2a
2b
The mixture 1a/1b has been employed for more than twenty years as an aromatic
substance and sold under the names Vertacal (Dragoco Gerberding & Co. AG,
Holzminden) and Floropal/Corps 717 (Haarmann & Reimer GmbH, Holzminden). In
the corresponding product specification sheets, the aroma of Vertacetal is described as

Helvetica Chimica Acta Vol. 86 (2003)
593
−fresh-herbal, typically the impression of grapefruit×, and the aroma of Floropal/
Corps 717 is described as −herbal-fresh, floral-green, similar to chrysanthemum, cyprus,
and grapefruit×. In 2000, Pickenhagen and co-workers [4] reported the odor properties
of the two diastereoisomers 1a and 1b. Ketal 1a was described as −strong, herbal-fresh,
green, and typical grapefruit×; 1b was found to be −very weak, chemical solvent-like×,
and to have a detracting influence upon the sensory properties of the mixture. They also
discovered, by in-house analyses, that the two commercial products differed with
respect to the relative content of the two diastereoisomers [4]: Vertacetal contained
54.38% of 1a and 44.33% of 1b, while Floropal contained 63.71% of 1a and 34.52% of
1b. They developed a procedure, based either on fractional distillation or on reaction
with BF3 ¥ Et2O, to enrich the mixture with the more valuable derivative 1a.
In the light of this interesting stereoselectivity in the odor perception of 1,3-dioxane
isomeric odorants, we decided to undertake the enzyme-mediated synthesis of the
enantiomers of compounds 1 and 2 to investigate the olfactory response of each single
isomer. This kind of investigation is part of a research program aimed to apply the
procedure of the so-called −chiral switch×, developed for drugs, to the fragrance industry
[5]. The use of the olfactory-active isomer of odorants would allow the elicitation of a
given odorous effect by adding a minor quantity of the chemical to the products of fine
and functional perfumery.
As for the choice of the method of optical activation, the enzyme-mediated
approach is particularly advantageous for the preparation of enantiomerically enriched
chiral odorants. These latter derivatives are usually scarcely functionalized compounds,
such as aldehydes, ketones, cyclic ethers, and lactones, often difficult to treat with the
methods of asymmetric catalysis. We had already shown in the past [5] the efficiency of
lipase-catalyzed kinetic resolution of suitable alcohol precursors in the synthesis of
enantiomerically pure single aromatic diastereoisomers. Herein we report the
usefulness of this approach for the preparation of the single isomers of 1 and 2, and
the olfactory properties of these compounds.
¾
2. Results and Discussion. 2.1. Floropal Isomers. Two different approaches to the
enantiomerically enriched isomers of Floropal were envisaged (Scheme 1). The first
was based on the enantiospecific reduction of diketone 3 to hydroxy ketone (S)-4
mediated by baker×s yeast (BY), and the second employed lipase-catalyzed kinetic
resolution of racemic 4 and of diastereoisomeric diols 5a and 5b.
Diketone 3 was submitted to BY fermentation according to the literature [6a], to
give (S)-4 showing an ee of 92%. This latter derivative was treated with MeMgI in
Et2O, providing a 1:1.25 mixture of the two diastereoisomeric diols (2 R,4S)-5a and
(2S,4S)-5b. Treatment of this mixture with acetaldehyde in CH2Cl2 solution in the
presence of a catalytic amount of p-toluenesulfonic acid (TsOH) afforded a 1:2
mixture of the two Floropal isomers (2S,4R,6S)-1a and (2S,4S,6S)-1b. When racemic
hydroxy ketone 4, prepared by aldol condensation of acetophenone and acetaldehyde
[7], was submitted to lipase-mediated esterification in tert-butyl methyl ether
(tBuOMe) solution, in the presence of vinyl acetate, acetate (R)-6 (ee 97%)1) and
unreacted alcohol (S)-4 (ee 93%) were recovered. Both (R)-6 and (S)-4 were
1
)
For the description of (Æ)-6, see [6b].

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 1
O
O
O
OH
i)
Ph
Ph
Ph
Ph
42%
(S)-4
3
O
OAc
O
OH
O
OH
ii)
+
+
Ph
4 (rac)
(S)-4
(37%)
(R)-6
(33%)
OH
O
OH
OH
HO
Ph
O
O
O
O
OH
iii)
iv)
+
83%
73%
Ph
Ph
Ph
(2S,4R,6S)-1a
Ph
(2S,4S,6S)-1b
(S)-4
(2R,4S)-5a
(2S,4S)-5b
O
O
O
O
OH
OH
OH
HO
O
OAc
iv)
+
iii)
+
89%
Ph
Ph
(2S,4R)-5a
Ph
78%
Ph
(2R,4S,6R)-1a
Ph
(2R,4R,6R)-1b
(2R,4R)-5b
(R)-6
ii)
43%
OAc
O
O
OH
v,iv)
Ph
Ph
(2R,4R)-7
82%
(2R,4R,6R)-1b
i) Baker×s yeast. ii) Lipase PS, tBuOMe, vinyl acetate. iii) 6 equiv. of MeMgI, Et2O; iv) MeCHO, CH2Cl2, TsOH.
v) KOH, MeOH.
submitted to MeMgI treatment, followed by reaction with acetaldehyde, to afford two
mixtures, one of enantiomerically pure (2R,4R,6R)-1b (66%) and (2R,4S,6R)-1a
(33%), and the other of enantiomerically pure (2S,4R,6S)-1a (33%) and (2S,4S,6S)-1b
(66%) (Scheme 1).
The mixture of diol derivatives (2S,4R)-5a and (2R,4R)-5b, prepared by reaction of
MeMgI with (R)-6, was submitted to enzyme-mediated transesterification under the
usual conditions, and a diastereoselective acetylation of (2R,4R)-5b was observed,
affording acetate (2R,4R)-7. This latter was hydrolyzed with KOH in MeOH, to provide
(2R,4R)-5b (ee > 99%; de 86%, i.e., (2R,4R)-5b/(2S,4R)-5a 93 :7), which was easily
converted to Floropal (2R,4R,6R)-1b (ee >99%; de 76%, i.e. (2R,4R,6R)-1b/
(2R,4S,6R)-1a 88 :12).
The two mixtures of enantiomerically pure diastereoisomers 1a and 1b were
enriched in the most valuable diastereoisomer by treatment with BF3 ¥ Et2O, according
to [4]. The following samples were obtained: a) from (2R,4R,6R)-1b (ee 97%, de 33%):
(2R,4S,6R)-1a (ee 80%, de 76%); b) from (2S,4S,6S)-1b (ee 93%, de 33%): (2S,4R,6S)-
1a (ee 68%, de 73%).

Helvetica Chimica Acta Vol. 86 (2003)
595
In the configurational assignment of these derivatives, (S) configuration at C(3) of
derivative (‡)-4 was established by comparison with literature data [6a]. The
configuration of this stereogenic C-atom was not altered in the sequence leading from
(S)-4 to Floropal stereoisomers 1a and 1b (MeMgI treatment and subsequent
ketalization). The relative configurations of the stereocenters of compounds 1a and
1b was defined by NMR spectroscopy, and confirmed by comparison with [4]. The
absolute configuration of the final Floropal stereoisomers was unambiguously
established2).
For derivative 1a, a clear NOE effect (8.3%) was observed between HÀC(2) and HÀC(6), and an
intensification of the signals of both HÀC(5) (1.0%, 2.8%) was obtained when MeÀC(4) was irradiated. In the
spectrum of derivative 1b, NOEs were observed between MeÀC(4) and HÀC(6) (9.4%) and HÀC(2) (13.1%).
¾
2.2. Magnolan Isomers. Prins reaction of 1H-indene with acetaldehyde in the
presence of formic acid and hydroquinone gave a mixture of only two racemic
diastereoisomers, whose relative configuration, depicted by structural formulas 2a [10]
and 2b (Scheme 2), was established by means of NMR spectroscopy.
In the NOE experiment with 2a, an intensification of the signals of HÀC(3) (8%), HÀC(4a) (1.9%), and
HÀC(9a) (7.6%) was obtained when HÀC(1) was irradiated3). NOEs were observed also between HÀC(9a)
and HÀC(4a) (5.4%) and HÀC(1) (6.6%). The vicinal coupling constant J(4a,9a) of 4.0 Hz was in accordance
with an equatorial location of HÀC(9a), and an axial location of HÀC(4a). For derivative 2b, NOEs were
observed between HÀC(3) and HÀC(1) (9.4%), and between HÀC(4a) and HÀC(9a) (5.2%)3). The values of
the vicinal coupling constants J(4a,9a) and J(9a,1) (6.4 and 10.5 Hz, resp.) were in accordance with an axial
location both of HÀC(9a) and HÀC(1), and with an equatorial location of HÀC(4a).
Hydrolysis of 2a and 2b to provide diol derivatives 8a [11] and 8b was troublesome
and proceeded with low yields. We found that NaBH4 reduction of racemic diketone 9,
prepared according to [12], gave a mixture that mainly contained (80%) the same diols
8a and 8b as those obtained by hydrolysis of the two products of the Prins reaction
2
)
These data on the configuration of (S)-4 and of the Floropal stereoisomers allowed us to determine the
absolute configuration of the intermediate diol (2R,4R)-5b (obtained by hydrolysis of acetate (2R,4R)-7).
Two contrasting values of specific rotation were reported in the literature for this compound. The
enantiomer (2R,4R) was described to show [a]D ˆ ‡25.4 (c ˆ 1.26, CHCl3) by Ruano et al. [8]. For the
enantiomer (2S,4S), the value [a]D ˆ ‡31.2 (c ˆ 1.0, CH2Cl2) was given by Yus et al. [9]. The 1H-NMR
spectra reported for the two enantiomers were different. In the same works, the enantiomers of the anti-
diol 5a were described: (2S,4R) with [a]D ˆ À21.5 (c ˆ 1.0, CHCl3) by Ruano et al. and (2R,4S) with [a]D
ˆ
À27.0 (c ˆ 1.0, CH2Cl2) by Yus et al.
The comparison of the 1H-NMR spectra of all these compounds revealed that the inconsistency in the
sign of the specific rotations arose from inversion of the syn/anti diastereoisomers. The 1H-NMR spectrum
of our compound 5b matched that described for syn-diol by Ruano et al. and for anti-diol by Yus et al. The
configuration at C(4) in our derivative (‡)-5b had to be R, because this compound was prepared starting
from (R)-6. The relative configuration of our diol could be deduced to be syn, since 5b gave Floropal 1b by
ketalization. It is true that ketalization in acid environment can produce epimerization at the benzylic
stereocenter via the carbocation. We describe in this work the conversion of 1b into 1a by BF3 ¥ Et2O
treatment. The formation of diastereoisomer 1a is thus favored under acid conditions. As a matter of fact,
diol (2R,4R)-5b (de 86%) gave Floropal 1b with lower diastereoisomeric excess (de 76%).
The numbering of the molecular skeleton of 2a, 2b, 13, and 14 is arbitrary; for systematic names, see Exper.
Part.
3
)

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2
3
O
O
O
O
+
1
9
2a (rac)3)
2b (rac)
i)
OH
OH
OH
OH
+
8a (rac)
8b (rac)
ii)
O
O
9 (rac)
i) HCl,THF (8a 12%, 8b 18%). ii) NaBH4, CH2Cl2/MeOH (8a 44%, 8b 36%).
(Scheme 2). Diols 8a and 8b were separated by column chromatography and submitted
separately to lipase-mediated acetylation with lipase PS and CCL as catalysts.
Interestingly enough, different regiochemistry and enantioselectivity were observed
with the two different enzymes (Scheme 3). When racemic diol 8a was treated with
CCL, diacetate (1R,2S,1'R)-10a (ee >99%), monoacetate (1R,2S,1'R)-11a (ee 92%),
and diol (1S,2R,1'S)-8a (ee 77%) were isolated. Treatment of racemic 8a with lipase PS
promoted the acetylation of the OH group in position 1' of the opposite enantiomer,
affording (1S,2R,1'S)-12a (ee 87.5%), and unreacted (1R,2S,1'R)-8a (ee 93%).
Different behavior was observed when racemic diol 8b was submitted to enzyme-
mediated transesterification. CCL Treatment provided diacetate (1S,2R,1'R)-10b (ee
>99%), monoacetate (1S,2R,1'R)-11b (ee 89%), and diol (1R,2S,1'S)-8b (ee 86%).
Lipase PS promoted the acetylation of 8b with the same enantioselectivity and
different regiochemistry, to afford monoacetate (1S,2R,1'R)-12b (ee 93%) and diol
(1R,2S,1'S)-8b (ee 93%).
Monoacetate derivatives (1S,2R,1'S)-12a (ee 87.5%) and (1S,2R,1'R)-12b (ee 93%)
were hydrolyzed, to afford diols (1S,2R,1'S)-8a and (1S,2R,1'R)-8b. Both the
enantiomers of 8a and 8b were converted to dioxane derivatives according to two
different procedures. When ketalization was performed with acetaldehyde in CH2Cl2
solution, in the presence of TsOH, inversion of the configuration at the benzylic C-
atom was observed in both diastereoisomeric diols. The following samples were
obtained (Scheme 4): a) from (‡)-8a (ee 93%): (À)-13 (95%, ee 90%) and other
Magnolan isomers (5%); b) from (À)-8a (ee 88%): (‡)-13 (87%, ee 88%) and other
Magnolan isomers (13%); c) from (‡)-8b (ee 93%): (À)-14 (90%, ee 94%) and other
Magnolan isomers (10%); d) from (À)-8b (ee 93%): (‡)-14 (94%, ee 87%) and other

Helvetica Chimica Acta Vol. 86 (2003)
597
Scheme 3
OH
OAc
OAc
OH
OAc
OH
i)
+
+
OH
(1R,2S,1'R)-10a
(1R,2S,1'R)-11a
(1S,2R,1'S)-8a
OH
8a (rac)
OH
OH
OH
OAc
ii)
+
(1R,2S,1'R)-8a
(1S,2R,1'S)-12a
OH
OAc
OAc
OH
OAc
OH
i)
+
+
OH
(1R,2S,1'S)-8b
(1S,2R,1'R)-11b
(1S,2R,1'R)-10b
OH
OH
OH
8b (rac)
OH
OAc
ii)
+
(1S,2R,1'R)-12b
(1R,2S,1'S)-8b
t
i) CCL, BuOMe, vinyl acetate. ii) Lipase PS, tBuOMe, vinyl acetate.
Magnolan isomers (6%). The relative configurations of these new −Magnolan
1
diastereoisomers× [10] were established by H-NMR spectroscopy.
In the NOE experiment with 13, NOEs were observed between HÀC(3) and HÀC(4a) (9.8%) and
between HÀC(1) and HÀC(9a) (8.2%). The values of the vicinal coupling constants J(4a,9a) and J(9a,1) (10.8
and 5.0 Hz, resp.) were in accordance with an axial location of both HÀC(9a) and HÀC(4a), and with an
equatorial location of HÀC(1). For derivative 14, intensification of the signals of HÀC(4a) (14.3%) and
HÀC(1) (5%) was obtained when HÀC(3) was irradiated. The value of the vicinal coupling constant J(4a,9a) of
10.2 was in accordance with an axial location of both HÀC(9a) and HÀC(4a).
The use of pyridium p-toluenesulfonate as a catalyst allowed us to prepare the
desired Magnolan isomers from the corresponding enantiomerically enriched diols,
with conservation of the configuration at the benzylic C-atom. The following samples
were obtained (Scheme 4): a) from (‡)-8a (ee 93%): (‡)-2a (95%) and other
Magnolan isomers (5%); b) from (À)-8a (ee 88%): (À)-2a (79%) and other Magnolan

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 4
O
O
OH
i)
OH
(+)-(1R,3R,4aR,9aS)-2a3)
65%
O
O
ii)
(+)-(1R,2S,1'R)-8a
81%
(-)-(1R,3S,4aS,9aS)-133)
O
O
i)
OH
OH
(-)-(1S,3S,4aR,9aS)-2b3)
58%
O
O
84%
(+)-(1R,2S,1'S)-8b
ii)
(-)-(1S,3S,4aS,9aS)-143)
i) MeCHO, CH2Cl2, pyridium p-toluenesulfonate. ii) MeCHO, CH2Cl2, TsOH.
isomers (21%); c) from (‡)-8b (ee 93%): (À)-2b (88%) and other Magnolan isomers
(12%); d) from (À)-8b (ee 93%): (‡)-2b (68%) and other Magnolan isomers (32%).
We also investigated a BY-mediated approach to the preparation of diols 8a and 8b,
which helped us in the assignment of the absolute configurations of the Magnolan
isomers. Racemic diketone 9 was submitted to BY fermentation. We assumed (S)
configuration for the stereocenter generated upon BY treatment, in analogy with the
stereochemical outcome of BY reduction of diketone 34). The 1:1mixture of the two
diastereoisomers (2R,1'S)-15a and (2S,1'S)-15b was reduced with NaBH4 to give mainly
(1S,2R,1'S)-8a (ee 94%) and (1R,2S,1'S)-8b (ee 94%) (Scheme 5). Chiral GC analysis
of the corresponding diacetate derivatives 10a and 10b allowed us to transfer this
assumption regarding configuration to the enantiomerically enriched diols obtained
through enzymic reactions, and to the Magnolan isomers prepared from them.
3. Olfactory Evaluation5). 3.1. Floropal Samples. The mixture (2S,4R,6S)-1a/
(2S,4S,6S)-1b 1:2 is more powerful than commercial Floropal, but it is also reminiscent
of 4,7,7-trimethyl-6-thiabicyclo[3.2.1]octane (Corps Pamplemousse), especially in its
4
)
A referee suggested that we tentatively ascertain the absolute configurations of derivatives 15a and 15b by
chemical correlation starting from known (2S,3R)-2-benzyl-3-hydroxybutanoic acid derivatives (see [13]).
Olfactory evaluations of the samples described were performed by Givaudan (A) and Dragoco perfumers (B).
5
)

Helvetica Chimica Acta Vol. 86 (2003)
599
Scheme 5
O
O
O
OH
OH
O
i)
+
39%
(2S,1'S)-15b
(2R,1'S)-15a
9 (rac)
OH
OH
OH
OH
ii)
+
78%
(-)-(1S,2R,1'S)-8a
(+)-(1R,2S,1'S)-8b
i) Baker×s yeast. ii) NaBH4, CH2Cl2, MeOH.
sulfury aspects (A); it is similar to the mixture (2R,4S,6R)-1a/(2R,4R,6R)-1b 1:2, but
not so pungent (B).
The mixture (2R,4S,6R)-1a/(2R,4R,6R)-1b 1:2 exhibits a more sulfury-sweaty
character (almost a bit of hydrogen sulfide), more technical in smell than the
corresponding mixture of enantiomers, yet still reminiscent of Floropal (A); it is green,
flowery, musty, strong, not very nice, pungent (B).
Isomer (‡)-(2R,4S,6R)-1a is slightly acidic, flowery, gardenia, slightly Vertacetal
(B).
Isomer (À)-(2S,4R,6S)-1a is Vertacetal, more like styrolyl acetate, with rhubarb note
(B).
Isomer (‡)-(2R,4R,6R)-1b has a pronounced floral character, sweet, reminiscent of
heliotropin and of the dry character of acetophenone (A); it is the weakest of the
Floropal samples, and it is slightly green (B).
Isomer (À)-(2S,4R,6S)-1a is the most interesting of the enantiomers of the valuable
diastereoisomer 1a. Its presence confers to the mixture (2S,4R,6S)-1a/(2S,4S,6S)-1b 1:2
a nice character, in spite of the major component being (2S,4S,6S)-1b.
Isomer (‡)-(2R,4R,6R)-1b with its pronounced floral character is quite different
from racemic 1b.
3.2. Magnolan Samples. Racemate (Æ)-2a is richer than commercial Magnolan, less
plastic, and more floral (A).
Racemate (Æ)-2b is the more powerful, much fresher than (Æ)-2a, and with an
additional pleasant marine tonality, also more substantive on blotter than (Æ)-2a (A).
Enantiomer (À)-2a is wet, earthy, greasy, technical (A).
Enantiomer (‡)-2a is reminiscent of caryophyllene, after 24 h very weak, with a
touch of woody character (A).
Enantiomer (‡)-2b is weak, acidic, floral, rosy, sweet, warm (A).
Enantiomer (À)-2b is rosy, floral (geranium, magnolia), citronellyl acetate, citric-
fruity, with a slightly green nuance; it is the most interesting enantiomer (A).
Enantiomer (À)-13 is odorless (A).
Enantiomer (‡)-13 is weak, with a sulfury character (off note) (A).
Enantiomer (‡)-14 is less powerful and less rich than all the other Magnolan
isomers (A).

600
Helvetica Chimica Acta Vol. 86 (2003)
Enantiomer (À)-14 is chemical and technical in smell, with even some sulfury side
notes; it is more powerful than the enantiomer (‡)-14 (A).
In the comparison of the two racemic diastereoisomers 2a and 2b, constituents of
commercial Magnolan, a difference in their odor response was found, just as it was
reported for the diastereoisomers 1a and 1b of Floropal [4]. The most appreciated
isomer 2b shows the phenyl moiety linked to C(4a) in an axial arrangement, resembling
the axial phenyl group of 1a (Fig.). Enantiomer (À)-2b is the most interesting
enantiomer of diastereoisomer 2b. The configuration of the three stereocenters is the
same as that observed in (À)-1a, the most appreciated of the 1a enantiomers (Fig.).
This could be expected based on the hypothesis of the interaction of these structurally
related odorants with the same chiral olfactory receptor.
Figure. Structural similarity of 2b and 1a
Enantiomers (‡)- and (À)-13, (‡)- and (À)-14 did not show any value as fragrant
substances. Fortunately, their formation is disfavored under the conditions of Prins
reaction.
4. Conclusions. This work presents another interesting example of stereoselection
in the odor perception of chiral odorants. The enantiomerically enriched isomers of the
dioxane odorants Floropal and Magnolan elicited different olfactory sensations.
Racemic 1a and 2b were found to show olfactory properties more pleasant than
those of the corresponding diastereoisomers 1b and 2a. The preparation of all the
enantiomerically pure isomers of (Æ)-1a, (Æ)-1b, (Æ)-2a, and (Æ)-2b by enzymic
methods allowed us also to establish that the enantiomers of these compounds are
differently recognized by the corresponding odor receptors. Interestingly, the best
Floropal and Magnolan enantiomers are characterized by the same absolute config-
uration.
The authors are indebted to Dr. Philip Kraft, Mrs. Caroline Denis, and Mr. Jan Jacques Rouge (Givaudan
D¸bendorf, Fragrance Research, Switzerland), and to Prof. Wilhelm Pickenhagen and Dr. Johannes Panten
(Dragoco Gerberding & Co. AG, Holzminden, Germany) for the odor descriptions. COFIN-Murst is
acknowledged for financial support.
Experimental Part
General. Hydroxy ketone 4 and diketone 9 were prepared according to [7][12]. Lipase PS Pseudomonas
cepacia (Amano Pharmaceuticals Co., Japan) and Candida rugosa lipase (Sigma) were employed in this work.
Chiral GC analyses: 25 m  0.25 mm Chirasil-DEX-CB (Chrompack) column, DANI-HT-86.10 gas chromato-
graph); tR in min; a) chiral GC of acetate 6: temp. program 408 (1min) À58/min À1508 (2 min) 108/min À1808
(5 min), tR ((S)-6) 20.64, tR ((R)-6) 20.77; b) chiral GC of diacetates 10a and 10b: temp. program 908 (1min)
À3.58/min À1208 À0.58/min À1358 (1min) À88/min À1808 (5 min), tR ((1R,2S,1'R)-10a) 26.22, tR ((1S,2R,1'S)-
10a) 26.54, tR ((1R,2S,1'S)-10b) 26.75, tR ((1S,2S,1'R)-10b) 27.99; c) chiral GC of Floropal samples 1a,b and

Helvetica Chimica Acta Vol. 86 (2003)
601
Magnolan samples 2a,b, 13, and 14: temp. program 508 (1min) À18/min À1208 À108/min À1808 (5 min), tR
((2R,4S,6R)-1a) 30.02, tR ((2S,4R,6S)-1a) 31 .1 7t,R (1b) 39.02, tR ((1R,3R,4aR,9aS)-2a) 56.95, tR ((1S,3S,4aS,9aR)-
2a) 56.37, tR ((1R,3R,4aS,9aR)-2b) 51.32, tR ((1S,3S,4aR,9aS)-2b) 51.72, tR ((1R,3R,4aR,9aR)-14) 52.22, tR
((1S,3S,4aS,9aS)-14) 55.42, tR ((1R,3S,4aS,9aS)-13) 60.71, tR ((1S,3R,4aR,9aR)-13) 55.32. GC/MS: HP-6890 gas
chromatograph equipped with a 5973 mass detector and a HP-5MS column (30 m  0.25 mm  0.25 mm); temp.
program: 608 (1min) À68/min À1508 (1min) À128/min À2808 (5 min). TLC: Merck silica gel 60 F254 plates.
1
Column chromatography (CC): silica gel. [a]D: Dr. Kernchen Propol digital automatic polarimeter. H-NMR
Spectra; CDCl3 solns. at r.t. unless otherwise stated; Bruker AC-250 spectrometer (250 MHz 1H); d in ppm rel.
to internal SiMe4; J values in Hz. Microanalyses: Analyzer 1106 Carlo Erba.
1,4a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ4,4a,5,9b-Tetrahydro-2,4-dimethylindeno[1,2-d]-
1,3-dioxin; 2a and 2b) [3]. A mixture of 90% formic acid (400 ml), acetaldehyde (280 ml), hexane (650 ml),
1H-indene (232 ml, 1.96 mol), and hydroquinone (0.75 g) was stirred at r.t. for 3 days. The mixture was poured
into H2O, the org. phase washed with H2O, sat. NaHCO3 soln. and H2O, dried (Na2SO4), and evaporated, and
the residue submitted to CC (hexane/AcOEt): 2a (156 g, 39%) followed by 2b (140 g, 35%).
Data of (1RS,3RS,4aRS,9aSR)-2a: chemical purity 86% by GC/MS (tR 18.25), with 7.9% of 2b and 6.1% of
1
an unidentified stereoisomer (m/z 204). H-NMR3): 7.50 7.10 (m, 4 arom. H); 4.92 (d, J ˆ 4, HÀC(4a)); 4.84
(q, J ˆ 5.0, HÀC(3)); 4.15 (dq, J ˆ 3.5, 6.4, HÀC(1)); 3.17 (dd, J ˆ 10.4, 15.0, 1 HÀC(9)); 2.75 (dd, J ˆ 6.9, 15.0,
‡
1 HÀC(9)); 2.08 (m, HÀC(9a)); 1.33 (m, MeÀC(3), MeÀC(1)). GC/MS: 204 (5, M ), 189 (14), 160 (16), 143
(95), 116 (100).
Data of (1RS,3RS,4aSR,9aRS)-2b: chemical purity 98% by GC/MS (tR 17.70), with 2% of 2a. 1H-NMR3):
7.56 7.00 (m, 4 arom. H); 5.47 (d, J ˆ 6.4, HÀC(4a)); 4.74 (q, J ˆ 4.9, HÀC(3)); 3.32 (dq, J ˆ 10.5, 6.0,
HÀC(1)); 2.91 (dd, J ˆ 6.4, 16.2, 1 HÀC(9)); 2.48 (d, J ˆ 16.2, 1 HÀC(9)); 2.40 (dt, J ˆ 10.5, 6.4, HÀC(9a));
‡
1.35 (d, J ˆ 4.9, MeÀC(3)); 1.26 (d, J ˆ 6.0, MeÀC(1)). GC/MS: 204 (7, M ), 189 (3), 143 (62), 116 (100).
(1RS,2SR,1'RS)- and (1RS,2SR,1'SR)-2-(1-Hydroxyethyl)indan-1-ol (ˆ(aRS,1RS,2SR)- and
(aRS,1SR,2RS)-2,3-Dihydro-1-hydroxy-a-methyl-1H-indene-2-methanol; 8a and 8b, resp.). Diketone
9
(100 g, 0.574 mol) was treated with NaBH4 (26.2 g, 0.690 mol) in CH2Cl2/MeOH 2 :1(400 ml). After the usual
workup, the residue was submitted to CC (hexane/AcOEt 5 :5): 8b (36.8 g, 36%), followed by 8a (44.9 g, 44%).
Data of 8b: M.p. 578. Chemical purity 98% by GC/MS (tR 19.37). 1H-NMR: 7.33 (m, 4 arom. H); 5.10
(d, J ˆ 7.5, HÀC(1)); 4.13 (m, MeCHOH); 3.01( dd, J ˆ 8.6, 15.7, 1 HÀC(3)); 2.75 (dd, J ˆ 9.4, 15.7, 1 HÀC(3));
‡
2.128 (m, HÀC(2)); 1.32 (d, J ˆ 6.4, Me). GC/MS: 178 (5, M ), 160 (56), 145 (100), 131 (37). Anal. calc. for
C11H14O2: C 74.13, H 7.92; found: C 74.31, H 7.68.
Data of 8a: M.p. 888. Chemical purity 97% by GC/MS (tR 19.53). 1H-NMR: 7.18 (m, 4 arom. H); 5.01
(d, J ˆ 7.1, H ÀC(1)); 4.00 (m, MeCHOH); 2.85 (dd, J ˆ 8.6, 15.7, 1 HÀC(3)); 2.63 (dd, J ˆ 9.0, 15.7, 1 HÀC(3));
‡
2.16 (m, HÀC(2)); 1.17 (d, J ˆ 6.4, Me). GC/MS: 178 (4, M ), 160 (57), 145 (100), 131 (35). Anal. calc. for
C11H14O2: C 74.13, H 7.92; found: C 73.98, H 8.10.
1. Baker×s Yeast Reduction. 1.1. General Procedure 1 (GP1). A suspension of baker×s yeast (2.5 kg) and d-
glucose (2.0 kg) in tap water (7.5 l) was stirred for 30 min at 328. A soln. of the suitable substrate (0.30 mol) in
EtOH (20 ml) was then added. After 48 h at r.t., Celite (1kg) was added, the mixture filtered, and the Celite pad
washed with AcOEt. The filtrate was adjusted to pH 4 with 2n HCl, and extracted with AcOEt. The org. layer
was dried (Na2SO4) and evaporated and the residue purified by CC (silica gel).
1.2. (‡)-(3S)-3-Hydroxy-1-phenylbutan-1-one ((S)-4). According to GP1, derivative 3 (48.6 g, 0.30 mol)
was submitted to yeast reduction. CC (hexane/AcOEt 7:3) gave (S)-4 (20.7 g, 42%). Chemical purity 92% by
GC/MS (tR 15.54); ee 92% (chiral GC of the corresponding acetate). [a]2D0 ˆ ‡67.4 (c ˆ 0.94, CHCl3) ([6a]:
1
[a]2D0 ˆ ‡68.4 (c ˆ 3.6, CHCl3)). H-NMR: 7.96 (m, 2 arom. H); 7.65 7.40 (m, 3 arom. H); 4.41( m, HÀC(3));
3.18 (dd, J ˆ 3, 17.8, HÀC(2)); 3.04 (dd, J ˆ 8.4, 17.8, HÀC(2)); 1.30 (d, J ˆ 6.4, Me). GC/MS: 164 (4), 146 (16),
120 (20), 105 (100).
1.3. (2R)- and (2S)-2,3-Dihydro-2-[(1S)-1-hydroxyethyl]-1H-inden-1-one ((2R,1'S)-15a and (2S,1'S)-15b,
resp.). According to GP1, from 9 (10.0 g, 0.057 mol). CC (hexane/AcOEt 7 :3) gave (2R,1'S)-15a/(2S,1'S)-15b
1:1(3.91g, 39%). 1H-NMR (deduced from the mixture): 7.80 7.30 (m, 8 arom. H); 4.49 (m, MeCHOH); 3.99
(m, MeCHOH); 3.38 3.08 (m, 2 H); 2.90 2.60 (m, 2 H); 1.30 (m, 2 Me). GC/MS: 1st diastereoisomer
(tR 18.78): 176 (1), 158 (21), 132 (100), 2nd diastereoisomer (tR 18.98): 176 (1), 158 (22), 132 (100). Anal. calc.
for C11H12O2: C 74.98, H 6.84; found: C 75.23, H 6.69.
2. Addition of Methylmagnesium Iodide to Ketone Derivatives. 2.1. General Procedure 2 (GP2). The
suitable ketone derivative (0.061mol) was added dropwise to a MeMgI soln. (from 0.366 mol of MeI and
0.335 mol of Mg) in Et2O (400 ml) at 108. The mixture was refluxed for 1h, poured into ice, quenched with sat.

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Helvetica Chimica Acta Vol. 86 (2003)
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. (2R,4S)- and (2S,4S)-2-Phenylpentane-2,4-diol ((2R,4S)-5a and (2S,4S)-5b, resp.). According to GP2,
from (S)-4 (10.0 g, 0.061 mol): (2R,4S)-5a/(2S,4S)-5b 1:1.25 (8.01g, 73%). 1H-NMR: 7.60 7.08 (m, arom. H);
4.29 (m, 1 HÀC(3) of 5b); 3.57 (m, 1 HÀC(3) of 5a); 2.05 1.71 (m, 2 H, HÀC(3) of 5a/5b); 1.64 (m, Me(1) of
5b); 1.50 (s, Me(1) of 5a); 1.17 (d, J ˆ 6.4, Me(5) of 5b); 1.07 (d, J ˆ 6.4, Me(5) of 5a). GC/MS: 5a (tR 16.19):
180 (1), 162 (18), 121 (100), 105 (84); 5b (tR 17.10): 180 (1), 165 (18), 121 (100), 105 (84).
2.3. (2R,4R)- and (2S,4R)-2-Phenylpentane-2,4-diol ((2R,4R)-5b and (2S,4R)-5a, resp.). According to GP2,
from (R)-6 (4.00 g, 0.019 mol): (2R,4R)-5b/(2S,4R)-5a 1:1(2.72 g, 78%). GC/MS and 1H-NMR: in accordance
with those described for (2R,4S)-5a/(2S,4S)-5b 1:1.25.
3. Lipase-Mediated Acetylation. 3.1. General Procedure 3 (GP 3). 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 chromatographed.
3.2. (3R)-3-Hydroxy-1-phenylbutan-1-one Acetate ((R)-6) and (3S)-3-Hydroxy-1-phenylbutan-1-one ((S)-
4). According to GP3 (lipase PS), from racemic 4 (10.0 g, 0.061 mol). CC (hexane/AcOEt 7:3) gave (R)-6
(4.15 g, 33%) and (S)-4 (3.70 g, 37%).
Data of (R)-6: Chemical purity 98% by GC/MS (tR 18.89); ee 97% (chiral GC). [a]2D0 ˆ ‡24.1( c ˆ 1.205,
1
CHCl3). H-NMR: 7.96 (m, 2 arom. H); 7.63 7.42 (m, 3 arom. H); 5.46 (sext., J ˆ 6.4, HÀC(3)); 3.44 (dd, J ˆ
6.4, 16.5, 1 HÀC(2)); 3.04 (dd, J ˆ 6.4, 16.5, 1 HÀC(2)); 2.0 (s, MeCOO); 1.36 (d, J ˆ 6.4, Me(4)). GC/MS: 163
‡
(11, [M À 43] ), 146 (7), 105 (100).
Data of (S)-4: Chemical purity 93% by GC/MS (tR 15.54); ee 93% (chiral GC of the corresponding
acetate). [a]2D0 ˆ ‡68.7 (c ˆ 1.01, CHCl3) ([6a]: [a]D20 ˆ ‡68.4 (c ˆ 3.6, CHCl3)). 1H-NMR and GC/MS: in
accordance with those described in 1.2.
3.3. (2R,4R)-2-Phenylpentane-2,4-diol 4-Acetate ((2R,4R)-7). According to GP3 (lipase PS), from
(2R,4R)-5b/(2S,4R)-5a 1:1 (2.00 g, 0.011mol). CC (hexane/AcOEt 7:3) gave (2 R,4R)-7 (1.05 g, 43%).
Chemical purity 93% by GC/MS (tR 18.36); ee >99% (chiral GC). [a]2D0 ˆ À5.45 (c ˆ 0.11, CHCl3); de 84%
(1H-NMR). 1H-NMR: 7.48 7.15 (m, 5 arom. H); 5.19 (m, CHOAc); 2.36 (dd, J ˆ 9.9, 15.0, HÀC(2)); 1.95
(dd, J ˆ 3.1, 15.0, HÀC(2)); 1.50 (s, Me); 1.47 (s, Me); 1.23 (d, J ˆ 6.3, Me(5)). 13C-NMR: 171.1; 147.4; 127.9;
126.2; 124.7; 72.8; 67.4; 49.0; 31.9; 21.4. GC/MS: 222 (1), 162 (28), 121 (100), 105 (89). Anal. calc. for C13H18O3:
C 70.24, H 8.10; found: C 70.41, H 7.95.
3.4. Enzyme-Mediated Acetylation of (1RS,2SR,1'RS)-Diol 8a. According to GP3, CCl-mediated
acetylation of diol 8a (22.0 g, 0.124 mol) gave the following products in order of elution (hexane/AcOEt
7:3): diacetate (1R,2S,1'R)-10a (4.04 g, 12%), monoacetate (1R,2S,1'R)-11a (4.38 g, 16%), and diol (1S,2R,1'S)-
8a (2.65 g, 12%).
Data of (1R,2S,1'R)-Acetic Acid 2-(1-Acetoxyethyl)indan-1-yl Ester (ˆ(aR,1R,2S)-1-(Acetyloxy)-2,3-
dihydro-a-methyl-1H-indene-2-methanol Acetate; (1R,2S,1'R)-10a): Chemical purity 98% by GC/MS (tR 21.95);
ee >99% (chiral GC). [a]2D0 ˆ ‡87.6 (c ˆ 1.57, CHCl3). 1H-NMR: 7.25 (m, 4 arom. H); 6.19 (d, J ˆ 5.7, HÀC(1));
5.13 (quint., J ˆ 6.4, CHOAc); 3.16 (dd, J ˆ 8.6, 15.9, 1 HÀC(3)); 2.83 (dd, J ˆ 6.9, 15.9, 1 HÀC(3)); 2.66
(m, HÀC(2)); 2.10 (s, AcO); 1.98 (s, AcO); 1.38 (d, J ˆ 6.4, MeCH). 13C-NMR: 170.9; 170.5; 142.1; 140.7; 128.9;
‡
126.9; 125.0; 124.7; 78.9; 70.5; 50.5; 31.2; 21.2; 18.0. GC/MS: 202 (8, [M À 60] ), 160 (82), 142 (100). Anal. calc.
for C15H18O4: C 68.68, H 6.92; found: C 68.56, H 6.79.
Data of (1R,2S,1'R)-Acetic Acid 2-(1-Hydroxyethyl)indan-1-yl Ester (ˆ(aR,1R,2S)-1-(Acetyloxy)-2,3-
dihydro-a-methyl-1H-indene-2-methanol; (1R,2S,1'R)-11a): Chemical purity 92% by GC/MS (tR 20.79); ee 92%
(chiral GC of the corresponding diacetate). [a]2D0 ˆ ‡98.6 (c ˆ 0.56, CHCl3). 1H-NMR: 7.26 (m, 4 arom. H); 6.23
(d, J ˆ 5.7, HÀC(1)); 4.06 (dq, J ˆ 4.9, 6.4, MeCHOH); 3.13 (dd, J ˆ 8.7, 16.4, 1 HÀC(3)); 2.87 (dd, J ˆ 7.2, 16.4,
1 HÀC(3)); 2.52 (m, HÀC(2)); 2.15 (s, AcO); 1.22 (d, J ˆ 6.4, Me). 13C-NMR: 171.8; 142.4; 140.5; 128.8; 126.8;
‡
124.8; 124.7; 79.2; 67.5; 53.7; 31.2; 21.3; 20.8. GC/MS: 220 (1, M ), 202 (1), 160 (36), 145 (50), 116 (100). Anal.
calc. for C13H16O3: C 70.89, H 7.32; found: C 70.77, H 7.51.
Data of (1S,2R,1'S)-2-(1-Hydroxyethyl)indan-1-ol (ˆ(aS,1S,2R)-2,3-Dihydro-1-hydroxy-a-methyl-1H-in-
dene-2-methanol; 1S,2R,1'S)-8a): Chemical purity 92% by GC/MS (tR 19.53); ee 77% (chiral GC of the
1
corresponding diacetate). [a]2D0 ˆ À16.6 (c ˆ 0.91, CHCl3). H-NMR and GC/MS: in accordance with those of
the racemate 8a (see above).
According to GP3, Lipase PS-mediated acetylation of diol 8a (22.0 g, 0.124 mol) gave the following
products in order of elution: monoacetate (1S,2R,1'S)-12a (6.01g, 24%) and diol (1 R,2S,1'R)-8a (6.84 g, 31%).
Data of (1S,2R,1'S)-2-(1-Acetoxyethyl)indan-1-ol (ˆ(aS,1S,2R)-2,3-Dihydro-1-hydroxy-a-methyl-1H-in-
dene-2-methanol a-Acetate; (1S,2R,1'S)-12a): Chemical purity 89% by GC/MS (tR 21.00); ee 87.5% (chiral GC

Helvetica Chimica Acta Vol. 86 (2003)
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of the corresponding diacetate). [a]2D0 ˆ À4 (c ˆ 0.485, CHCl3). 1H-NMR: 7.37 (m, arom. H); 7.26 (m,
3arom. H); 5.29 (quint., J ˆ 6.2, MeCHOAc); 4.97 (d, J ˆ 7.3, HÀC(1)); 3.13 (dd, J ˆ 8.4, 15.8, 1 HÀC(3)); 2.77
(dd, J ˆ 9.6, 15.8, 1 HÀC(3)); 2.38 (m, HÀC(2)); 2.04 (s, AcO); 1.37 (d, J ˆ 6.2, Me). 13C-NMR: 171.4; 145.0;
‡
141.2; 128.4; 127.2; 125.1; 124.5; 77.5; 67.9; 55.3; 31.7; 21.6; 19.3. GC/MS: 202 (1, M ), 160 (56), 145 (100), 131
(38). Anal. calc. for C13H16O3: C 70.89, H 7.32; found: C 70.74, H 7.23.
Data of (1R,2S,1'R)-8a: Chemical purity by GC/MS (tR 19.53); ee 93.1% (chiral GC of the corresponding
1
diacetate). [a]2D0 ˆ ‡20.4 (c ˆ 0.69, CHCl3). H-NMR and GC/MS: in accordance with those of the racemate.
3.5. Enzyme-Mediated Acetylation of Diol (1RS,2SR,1'SR)-8b. According to GP3, CCL treatment of diol
8b (18.0 g, 0.101 mol) gave the following products in order of elution: diacetate (1S,2R,1'R)-10b (2.91 g, 11%),
monoacetate (1S,2R,1'R)-11b (3.33 g, 15%), and diol (1R,2S,1'S)-8b (3.23 g, 18%).
Data of (1S,2R,1'R)-Acetic Acid 2-(1-Acetoxyethyl)indan-1-yl Ester (ˆ(aR,1S,2R)-1-(Acetyloxy)-2,3-
dihydro-a-methyl-1H-indene-2-methanol Acetate; (1S,2R,1'R)-10b): Chemical purity 86% by GC/MS (tR 21.9);
ee >99% (chiral GC). [a]2D0 ˆ ‡95.7 (c ˆ 0.68, CHCl3). 1H-NMR: 7.30 7.15 (m, 4 arom. H); 6.31( d, J ˆ 5.1,
HÀC(1)); 5.08 (quint., J ˆ 6.4, CHOAc); 3.17 (m, 1 HÀC(3)); 2.71( m, 1 HÀC(3), HÀC(2)); 2.11 (s, AcO);
1.97 (s, AcO); 1.29 (d, J ˆ 6.4, Me). 13C-NMR: 170.7; 170.5; 141.9; 140.8; 128.9; 127.1; 125.1; 124.6; 79.0; 71.7;
‡
50.5; 33.1; 21.2; 21.3; 18.3. GC/MS: 202 (5, [M À 60] ), 160 (45), 142 (100). Anal. calc. for C15H18O4: C 68.68,
H 6.92; found: C 68.47, H 6.88.
Data of (1S,2R,1'R)-Acetic Acid 2-(1-Hydroxyethyl)indan-1-yl Ester (ˆ(aR,1S,2R)-1-(Acetyloxy)-2,3-
dihydro-a-methyl-1H-indene-2-methanol; (1S,2R,1'R)-11b): Chemical purity 89% by GC/MS (tR 20.81); ee 89%
(chiral GC of the corresponding diacetate). [a]2D0 ˆ ‡51.3 (c ˆ 0.635, CHCl3). 1H-NMR: 7.26 (m, arom. H); 6.29
(d, J ˆ 5.0, HÀC(1)); 3.87 (dq, J ˆ 8.5, 6.2, MeCHOH); 3.20 (dd, J ˆ 8.5, 16.2, 1 HÀC(3)); 2.68 (dd, J ˆ 6.9, 16.2,
1 HÀC(3)); 2.48 (m, HÀC(2)); 2.14 (s, AcO); 1.26 (d, J ˆ 6.2, Me). 13C-NMR: 172.0; 142.4; 140.2; 128.9; 126.9;
125.1; 123.9; 80.4; 69.5; 53.6; 33.5; 21.4. GC/MS: 220 (1), 202 (1), 177 (13), 160 (28), 145 (49), 116 (100). Anal.
calc. for C13H16O3: C 70.89, H 7.32; found: C 70.75, H 7.48.
Data of (1R,2S,1'S)-2-(1-Hydroxyethyl)indan-1-ol (ˆ(aS,1R,2S)-2,3-Dihydro-1-hydroxy-a-methyl-1H-in-
dene-2-methanol; (1R,2S,1'S)-8b): Chemical purity 87% by GC/MS (tR 19.37); ee 86% (chiral GC of the
1
corresponding diacetate). [a]2D0 ˆ ‡7.98 (c ˆ 0.601, CHCl3). H-NMR and GC/MS spectra: in accordance with
those of the racemate.
According to GP3, lipase-PS-mediated acetylation of diol 8b (18.0 g, 0.101 mol) gave the following
products in order of elution: monoacetate (1S,2R,1'R)-12b (7.95 g, 39%) and diol (1R,2S,1'S)-8b (5.75 g, 32%).
Data of (1S,2R,1'R)-2-(1-Acetoxyethyl)indan-1-ol (ˆ(aR,1S,2R)-2,3-Dihydro-1-hydroxy-a-methyl-1H-in-
dene-2-methanol a-Acetate; (1S,2R,1'R)-12b): Chemical purity 92% by GC/MS (tR 20.91); ee 93% (chiral GC of
the corresponding diacetate). [a]2D0 ˆ À7.24 (c ˆ 0.525, CHCl3). 1H-NMR: 7.37 (m, arom. H); 7.23 (m, 3 ar-
om. H); 5.15 (m, MeCHOAc, HÀC(1)); 3.06 (dd, J ˆ 8.7, 15.8, 1 HÀC(3)); 2.62 (dd, J ˆ 9.0, 15.8, 1 HÀC(3));
2.45 (m, HÀC(2)); 2.08 (s, AcO); 1.36 (d, J ˆ 6.4, Me). 13C-NMR: 170.6; 144.2; 140.2; 127.7; 126.5; 124.1; 123.8;
‡
77.5; 72.3; 53.9; 32.3; 20.9; 18.3. GC/MS: 202 (2, M ), 160 (54), 145 (100), 131 (35). Anal. calc. for C13H16O3:
C 70.89, H 7.32; found: C 71.02, H 7.48.
Data of Diol (1R,2S,1'S)-8b: Chemical purity 85% by GC/MS (tR 19.37); ee 93.0% (chiral GC of the
corresponding diacetate). [a]2D0 ˆ ‡8.74 (c ˆ 0.595, CHCl3). 1H-NMR and GC/MS: in accordance with those of
the racemate.
4. Acetals from Enantiomerically Enriched Diols, Catalyzed by p-Toluenesulfonic Acid. 4.1. General
Procedure 4 (GP4). A mixture of the suitable diol (0.014 mol), acetaldehyde (1 ml), and TsOH (100 mg) in
CH2Cl2 was stirred at r.t. overnight. The mixture was poured into H2O, the org. phase dried (Na2SO4) and
evaporated, and the residue chromatographed (hexane/AcOEt 95 :5).
4.2. (2S,4R,6S)- and (2S,4S,6S)-2,4,6-Trimethyl-4-phenyl-1,3-dioxane ((2S,4R,6S)-1a and (2S,4S,6S)-1b,
resp.). According to GP4, (2R,4S)-5a/(2S,4S)-5b 1:1 (7.90 g, 0.044 mol) gave (2 S,4R,6S)-1a/(2S,4S,6S)-1b 1:2
(7.32 g, 81%); ee 93% (chiral GC). [a]2D0 ˆ À49.5 (c ˆ 1.21, CHCl3). 1H-NMR: 7.56 7.16 (m, arom. H); 5.19
(q, J ˆ 5.0, HÀC(2)(1b)); 4.70 (q, J ˆ 5.2, HÀC(2)(1a)); 4.02 (m, HÀC(6)(1b)); 3.67 (m, HÀC(6(1a)); 2.35
(dd, J ˆ 1.8, 13.8, 1 HÀC(5)(1a)); 1.81 (dd, J ˆ 2.5, 13.1, 1 HÀC(5)(1b)); 1.70 (dd, J ˆ 11.6, 13.8,
1 HÀC(5)(1a)); 1.67 1.55 (m, 1 HÀC(5) and MeÀC(4)(1b)); 1.42 (s ‡ d, J ˆ 5.0, MeÀC(4)(1a),
MeÀC(2)(1b)); 1.35 (d, J ˆ 5.2, MeÀC(2)(1a)); 1.24 (d, J ˆ 6.4, MeÀC(6)(1b)); 1.23 (d, J ˆ 6.4,
‡
MeÀC(6)(1a)). GC/MS: 1a (tR 14.66): 206 (0.5, M ), 191 (9), 146 (64), 131 (68), 105 (100); 1b (tR 16.17):
‡
206 (1, M ), 191 (39), 162 (26), 145 (30), 105 (100).
4.3. (2R,4R,6R)- and (2R,4S,6R)-2,4,6-Trimethyl-4-phenyl-1,3-dioxane ((2R,4R,6R)-1b and (2R,4S,6R)-1a,
resp.). According to GP4, (2R,4R)-5b/(2S,4R)-5a 1:1.25 (2.60 g, 0.014 mol) gave (2 R,4R,6R)-1b/(2R,4S,6R)-1a

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2 :1(2.57 g, 89%); ee 97% (chiral GC). [ a]2D0 ˆ ‡55.4 (c ˆ 1.3, CHCl3). H-NMR and GC/MS: in accordance
with those described in 4.2.
4.4. (2R,4R,6R)-2,4,6-Trimethyl-4-phenyl-1,3-dioxane ((2R,4R,6R)-1b). According to GP4, (2R,4R)-5b
(0.700 g, 3.88 mmol) gave (2R,4R,6R)-1b (0.680 g, 85%); ee >99% (chiral GC); de 76% (GC/MS). [a]D20
ˆ
‡44.5 (c ˆ 1.29, CHCl3). 1H-NMR: 7.48 7.20 (m, 4 arom. H); 5.19 (q, J ˆ 5.0, HÀC(2)); 4.02 (m, HÀC(6));
1.81 (dd, J ˆ 2.5, 13.1, HÀC(5)); 1.67 1.55 (m, HÀC(5), MeÀC(4)); 1.42 (d, J ˆ 5.0, MeÀC(2)); 1.24 (d, J ˆ
6.4, MeÀC(6)). GC/MS: in accordance with that described in 4.2.
4.5. (1R,3S,4aS,9aS)-1,4a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2S,4R,4aS,9bS)-4,4a,5,9b-Tet-
rahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; (1R,3S,4aS,9aS)-13). According to GP4, (1R,2S,1'R)-8a (3.35 g,
0.019 mol) gave (1R,3S,4aS,9aS)-13 (3.10 g, 81%). M.p. 408. Chemical purity 95% by GC/MS (tR 19.25); ee 90%
(chiral GC). [a]D20 ˆ À10.97 (c ˆ 0.93, CHCl3). 1H-NMR3): 7.41 7.13 ( m, 4 arom. H); 5.25 (q, J ˆ 5.4, HÀC(3));
4.93 (d, J ˆ 10.8, HÀC(4a)); 4.51( dq, J ˆ 5.0, 7.0, HÀC(1)); 2.76 (dd, J ˆ 6.4, 14.3, 1 HÀC(9)); 2.64
(m, HÀC(9a)); 2.40 (t, J ˆ 14.3, 1 HÀC(9)); 1.44 (d, J ˆ 7.0, MeÀC(1)); 1.42 (d, J ˆ 5.4, MeÀC(3)). GC/MS:
204 (15), 203 (2), 160 (35), 143 (30), 132 (70), 117 (100). Anal. calc. for C13H16O2: C 76.44, H 7.90; found:
C 76.32, H 7.77.
4.6. (1S,3R,4aR,9aR)-1,4a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2R,4S,4aR,9bR)-4,4a,5,9b-
Tetrahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; (1S,3R,4aR,9aR)-13). According to GP4, (1S,2R,1'S)-8a
(2.35 g, 0.013 mol) gave (1S,3R,4aR,9aR)-13 (2.31g, 85%). Chemical purity 87% by GC/MS ( tR 19.25); ee
88% (chiral GC). [a]2D0 ˆ ‡8.26 (c ˆ 0.775, CHCl3). 1H-NMR and GC/MS: in accordance with those of its
enantiomer. Anal. calc. for C13H16O2: C 76.44, H 7.90; found: C 76.53, H 8.03.
4.7. (1R,3R,4aR,9aR)-1,4a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2R,4R,4aR,9bR)-4,4a,5,9b-
Tetrahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; 1R,3R,4aR,9aR)-14). According to GP4, (1S,2R,1'R)-8b
(3.80 g, 0.021mol) gave (1 R,3R,4aR,9aR)-14 (3.47 g, 79%). Chemical purity 94% by GC/MS (tR 18.00); ee
87% (chiral GC). [a]2D0 ˆ ‡16.35 (c ˆ 0.685, CHCl3). 1H-NMR3): 7.42 7.14 (m, 4 arom. H); 5.03 (q, J ˆ 5.3,
HÀC(3)); 4.58 (d, J ˆ 10.2, HÀC(4a)); 3.98 (m, HÀC(1)); 2.81 (dd, J ˆ 6.6, 14.6, 1 HÀC(9)); 2.40 (t, J ˆ 14.6,
1 HÀC(9)); 1.96 (m, HÀC(9a)); 1.48 (d, J ˆ 5.03, MeÀC(3)); 1.24 (d, J ˆ 6.2, MeÀC(1)). GC/MS: 204 (6), 203
(5), 160 (10), 143 (15), 131 (31), 115 (100). Anal. calc. for C13H16O2: C 76.44, H 7.90; found: C 76.60, H 7.75.
4.8. (1S,3S,4aS,9aS)-1,4a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2S,4S,4aS,9bS)-4,4a,5,9b-Tet-
rahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; (1S,3S,4aS,9aS)-14). According to GP4, (1R,2S,1'S)-8b (1.55 g,
8.7 mmol) gave (1S,3S,4aS,9aS)-14 (1.51 g, 84%). Chemical purity 90% by GC/MS (tR 18.00); ee 94% (chiral
GC). [a]2D0 ˆ À13.3 (c ˆ 0.685, CHCl3). 1H-NMR and GC/MS: in accordance with those of its enantiomer. Anal.
calc. for C13H16O2: C 76.44, H 7.90; found: C 76.33, H 7.68.
5. Acetals from Enantiomerically Enriched Diols, Catalyzed by Pyridinium p-Toluenesulfonate. 5.1. General
Procedure 5 (GP5). A mixture of the suitable diol (0.013 mol), acetaldehyde (1 ml), and pyridinium p-
toluenesulfonate (100 mg) in CH2Cl2 was stirred at r.t. overnight. The mixture was poured into H2O, the org.
phase dried (Na2SO4) and evaporated, and the residue chromatographed (hexane/AcOEt 95 :5).
5.2. (1S,3S,4aS,9aR)-1,4a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2S,4S,4aR,9bS)-4,4a,5,9b-Tet-
rahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; (1S,3S,4aS,9aR)-2a). According to GP5, (1S,2R,1'S)-8a (2.35,
0.013 mol) gave (1S,3S,4aS,9aR)-2a (1.85 g, 68%). Chemical purity 79% by GC/MS (tR 18.25); ee 82% (chiral
GC). [a]2D0 ˆ À57.4 (c ˆ 0.575, CHCl3). 1H-NMR and GC/MS: in accordance with those of the racemate.
5.3. (1R,3R,4aR,9aS)-1,4a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2R,4R,4aS,9bR)-4,4a,5,9b-
Tetrahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; (1R,3R,4aR,9aS)-2a). According to GP5, (1R,2S,1'R)-8a
(3.35 g, 0.019 mol) gave (1R,3R,4aR,9aS)-2a (2.52 g, 65%). Chemical purity 95% by GC/MS (tR 18.25); ee
92% (chiral GC). [a]2D0 ˆ ‡74.6 (c ˆ 0.845, CHCl3). 1H-NMR and GC/MS: in accordance with those of the
racemate.
5.4. (1R,3R,4aS,9aR)-1,4a,4b,8a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2R,4R,4aR,9bS)-
4,4a,5,9b-Tetrahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; (1R,3R,4aS,9aR)-2b). According to GP5,
(1S,2R,1'R)-8b (3.80 g, 0.021mol) gave (1 R,3R,4aS,9aR)-2b (2.77 g, 63%). Chemical purity 68% by GC/MS
(tR 17.70); ee 89% (chiral GC). [a]2D0 ˆ ‡68.9 (c ˆ 0.47, CHCl3). 1H-NMR and GC/MS: in accordance with those
of the racemate.
5.5. (1S,3S,4aR,9aS)-1,4a,4b,8a,9,9a-Tetrahydro-1,3-dimethyl-2,4-dioxafluorene (ˆ(2S,4S,4aS,9bR)-
4,4a,5,9b-Tetrahydro-2,4-dimethylindeno[1,2-d]-1,3-dioxin; (1S,3S,4aR,9aS)-2b). According to GP5,
(1R,2S,1'S)-8b (1.55 g, 8.7 mmol) gave (1S,3S,4aR,9aS)-2b (1.04 g, 58%). Chemical purity 88% by GC/MS
(tR 17.70); ee ˆ 89% (chiral GC). [a]2D0 ˆ À80.3 (c ˆ 0.65, CHCl3). 1H-NMR and GC/MS: in accordance with
those of the racemate.

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6. Inversion of Floropal Samples withBF 3 ¥ Et2O. 6.1. General Procedure 6 (GP6). A soln. of the suitable
Floropal sample (25 g) in CH2Cl2 (25 ml) was treated at 208 under N2 with BF3 ¥ Et2O (0.5 g). The mixture was
stirred at r.t. for 7 h, washed to neutrality with 5% (w/w) NaOH soln., dried (Na2SO4), and evaporated. The
residue was chromatographed (hexane).
6.2. (2R,4S,6R)-2,4,6-Trimethyl-4-phenyl-1,3-dioxane ((2R,4S,6R)-1a). According to GP6, (2R,4S,6R)-1a/
(2R,4R,6R)-1b 1:2 (2.0 g, 9.7 mmol) gave (2 R,4S,6R)-1a (1.06 g, 53%); ee 80% (chiral GC); de 76%. [a]D20
ˆ
‡59 (c ˆ 1.37, CHCl3). 1H-NMR: 7.48 7.20 (m, 4 arom. H); 4.70 (q, J ˆ 5.2, HÀC(2)); 3.67 (m, HÀC(6));
2.35 (dd, J ˆ 1.8, 13.8, 1 HÀC(5)); 1.70 (dd, J ˆ 11.6, 13.8, 1 HÀC(5)); 1.42 (s, MeÀC(4)); 1.35 (d,
‡
J ˆ 5.2, MeÀC(2)); 1.23 (d, J ˆ 6.4, MeÀC(6)). GC/MS (tR 14.66): 206 (0.5, M ), 191 (9), 146 (64), 131 (68),
105 (100).
6.3. (2S,4R,6S)-2,4,6-Trimethyl-4-phenyl-1,3-dioxane ((2S,4R,6S)-1a). According to GP6, (2S,4R,6S)-1a/
(2S,4S,6S)-1b 1:2 (2.0 g, 9.7 mmol) gave (2S,4R,6S)-1a. (1.36 g, 68%); ee 68% (chiral GC); de 73%. [a]D20
À50.2 (c ˆ 1.29, CHCl3). 1H-NMR and GC/MS: in accordance with those of the enantiomer.
ˆ
7. Hydrolyses. 7.1. (2R,4R)-2-Phenylpentane-2,4-diol ((2R,4R)-5b). Acetate (2R,4R)-7 (0.95 g, 4.27 mmol)
was hydrolyzed with KOH (0.359 g, 6.42 mmol) in MeOH (20 ml): (2R,4R)-5b (0.745 g, 97%). Chemical purity
94% by GC/MS (tR 17.10); ee >99% (chiral GC of the corresponding diacetate). [a]2D0 ˆ ‡15.84 (c ˆ 0.265,
CHCl3); de 86% (GC/MS). 1H-NMR: 7.60 7.08 (m, arom. H); 4.29 (m, HÀC(3)); 1.81 (m, CH2); 1.64
(s, Me(1)); 1.17 (d, J ˆ 6.4, Me(5)). GC/MS: 180 (1), 165 (18), 121 (100), 105 (84).
7.2. (1S,2R,1'S)-2-(1-Hydroxyethyl)indan-1-ol (ˆ(aS,1S,2R)-2,3-Dihydro-1-hydroxy-a-methyl-1H-indene-
2-methanol; (1S,2R,1'S)-8a). Acetate (1S,2R,1'S)-12a (5.80 g, 0.029 mol) was hydrolyzed with KOH (2.44 g,
0.043 mol) in MeOH (40 ml): (1S,2R,1'S)-8a (5.00 g, 98%); ee 93% (GC of the corresponding diacetate).
[a]2D0 ˆ À18.8 (c ˆ 0.891, CHCl3). 1H-NMR and GC/MS: in accordance with those of the racemate.
7.3. (1S,2R,1'R)-2-(1-Hydroxyethyl)indan-1-ol (ˆ(aR,1S,2R)-2,3-Dihydro-1-hydroxy-a-methyl-1H-in-
dene-2-methanol; (1S,2R,1'R)-8b). Acetate (1S,2R,1'R)-12b (7.80 g, 0.039 mol) was hydrolyzed with KOH
(3.28 g, 0.058 mol) in MeOH (40 ml): (1S,2R,1'R)-8b (6.67 g, 97%); ee >99% (chiral GC of the correspond-
ing diacetate). [a]2D0 ˆ À8.80 (c ˆ 0.661, CHCl3). 1H-NMR and GC/MS: in accordance with those of the
racemate.
8. (1S,2R,1'S)- and (1R,2S,1'S)-2-(1-Hydroxyethyl)indan-1-ol ((1S,2R,1'S)-8a and (1R,2S,1'S)-8b, resp.).
The mixture (2R,1'S)-15a/(2S,1'S)-15b 1:1 (3.80 g, 0.022 mol) was submitted to NaBH 4 reduction: mixture
(3.05, 78%) containing (1S,2R,1'S)-8a (ee 94%, chiral GC of the corresponding diacetate) and (1R,2S,1'S)-8b
(ee 94% of the corresponding diacetate) in 1:1 ratio.
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Received September 9, 2002