Enzymatic approach to and odor description of the twelve enantiomerically pure isomers of Pelargene

Article abstract of DOI:10.1002/hlca.200690020

Pelargene is a commercial fragrance sold as a mixture of three regioisomeric pyran derivatives (1-3). The enantiomers of each of the two possible diastereoisomers of 1-3 were prepared by means of a biocatalyzed approach, and the odor properties of the twe

Full text of DOI:10.1002/hlca.200690020

Helvetica Chimica Acta – Vol. 89 (2006)
177
Enzymatic Approach to and Odor Description of the Twelve Enantiomerically
Pure Isomers of Pelargene®
by Agnese Abate, Maurizio Allievi, Elisabetta Brenna*, Claudio Fuganti, Francesco G. Gatti,
and Stefano Serra
Dipartimento di Chimica, Materiali ed Ingegneria Chimica, Politecnico di Milano, CNR – Istituto del
Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano
(phone: ++39-0223993077; fax: ++39-0223993080; e-mail: elisabetta.brenna@polimi.it)
Pelargene® is a commercial fragrance sold as a mixture of three regioisomeric pyran derivatives
(1–3). The enantiomers of each of the two possible diastereoisomers of 1–3 were prepared by means
of a biocatalyzed approach, and the odor properties of the twelve isolated stereoisomers were evaluated.
Introduction. – In 2004, Richard Axel and Linda Buck were awarded the Nobel Prize in
Physiology or Medicine [1] for their discoveries of ‘odorant receptors and the organiza-
tion of the olfactory system’. In their seminal work published in Cell in 1991 [2], they
explained how the mammalian olfactory system can recognize and discriminate a
large number of different odorant molecules. The detection of chemically distinct odor-
ants presumably results from the association of odorous ligands with specific receptors
in the ciliary membrane of olfactory neurons. Axel and Buck showed that 3% of our
genes are used to code for the different odorant receptors on the membrane of the
olfactory receptor cells. When an odorant receptor is activated by an odorous sub-
stance, an electric signal is triggered in the olfactory receptor cell, and sent to the
brain via nerve processes. Axel and Buck showed that the large family of odorant recep-
tors belongs to the G-protein-coupled receptors (GPCR).
Recently, Hatt and co-workers [3] cloned, functionally expressed, and characterized
some of the human olfactory receptors from chromosome 17. They showed that a
receptor protein is capable of recognizing the particular substructure of an odorous
molecule and, therefore, is able to respond only to odorants that have a defined molec-
ular structure.
Most odors are due to several odorant molecules, and each odorant molecule, in
turn, activates several odorant receptors, which gives rise to a so-called ‘odorant pat-
tern’ [4]. This pattern is interpreted and leads to the conscious experience of a recog-
nizable odor. Until these findings, very little had been known about the molecular basis
of odor detection: the structural features of odorous molecules are fundamental in
determining the interaction and the activation of the G-protein.
During the last years, we have been investigating the effects of the absolute config-
uration of chiral molecules on their odor properties [5]. We expect that the spatial dis-
position of the substituents around a stereogenic element could influence the way in
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

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which the molecule interacts with the olfactory receptors. Since we are ‘chiral being’s,
we should, in principle, be able to distinguish chiral molecules by their odor.
Herein, we report the preparation and odor description of all twelve possible ster-
eoisomers of Pelargene®, which is widely used in perfumery.
Results and Discussion. – Pelargene (Quest International) is a floral fragrance with a
powerful odor reminding of the crushed leaves of the Pelargonium plant, which is com-
monly known as house-geranium. A subtle spicy-floral undertone supports the main
character. It combines very well with floral notes; it is extremely fiber substantive,
and can be used over quite a wide pH range. Commercial Pelargene is a mixture of
the three main regioisomers 1–3. According to an in-house GC/MS analysis, the com-
position of the commercial mixture is as follows: 73.7% cis-1, 1.7% cis-2, 17.7% cis-3,
0.4% trans-2, 0.8% trans-3, and 5.7% of unknown constituents.
1. Synthesis. We first performed a literature search for the synthesis of this kind of
substituted dihydropyrans. Sequin and Schneider had re-investigated in 1985 [6] the
products obtained by Prins reaction of 4-methylpent-4-en-2-ol with benzaldehyde1).
The authors reported that, when the reaction is catalyzed by H2SO4, the two tetrahydro-
pyranols cis-(2RS,4RS,6RS)-4 and cis-(2RS,4SR,6RS)-4 are obtained as a 1:2 mixture
1
(Scheme 1). The relative configuration was assigned on the basis of H- and 13C-
NMR spectra2).
Dehydration of both the stereoisomers 4 over KHSO4 gave a mixture of olefins,
80% of which consisted of cis-1, as inferred from the typical resonance of the methyl-
idene group at d(H) 4.78 in the 1H-NMR spectrum. When the dehydration was carried
out by heating the two tetrahydropyranols with 20% H2SO4 at 1208 for 6 h, mainly cis-
and trans-3 were obtained3). The authors assumed that the dehydration with H2SO4 led
first to cis-3, where the relative configuration at C(2) and C(6) was the same of the start-
1
)
)
This reaction had been previously described in several publications [7].
2
HꢀC(2) and HꢀC(6) showed – besides the coupling of HꢀC(2) with the neighboring Me group –
coupling to CH2(3) and CH2(5), resp., with J values of ca. 11 and 3 Hz, which indicated that the
Me and Ph groups were both in equatorial position. The signals of the axial H-atoms at C(2) and
C(6) in cis-(2RS,4RS,6RS)-4 were observed at lower field than the corresponding resonances in
the other stereoisomer, suggesting that the 4-OH group was also in axial position. This assignment
was corroborated by 13C-NMR: the signal of the axial Me group at C(4) in cis-(2RS,4SR,6RS)-4
was shifted upfield by 5.6 ppm as compared to the same resonance in the spectrum of cis-
(2RS,4RS,6RS)-4.
3
)
Both compounds showed a dd for HꢀC(6), and HꢀC(2) gave rise to a m, which could be interpreted
as a q broadened by the small homoallylic coupling.

Helvetica Chimica Acta – Vol. 89 (2006)
179
Scheme 1
ing pyranols. This compound then epimerized to trans-3 via ring opening. They did not
observe the formation of any product showing the C=C bond in 4,5-position, i.e., cis-
and trans-2.
Both cis- and trans-3 could be prepared also by Diels–Alder reaction of benzalde-
hyde with 2-methylpenta-1,3-diene under different conditions, e.g., in the presence of
1) AlCl3 [8], 2) cationic Pd complexes [9], 3) BF3 ·Et2O [10], or 4) triflic acid
(CF3SO3H) [11].
In another approach, trans-3 had been obtained by treatment of 2-phenyl-4-[(4-
methylphenyl)sulfonyl]-3,4-dihydro-2H-pyran with BuLi and MeI, followed by reac-
tion with Me3Al [12]. And cis-2 can be prepared by reduction of the corresponding
pyrilium salt with triacetoxyborohydride [13]. Finally, cis-1 was obtained by a proce-
dure of a Lewis acid promoted allylsilane–acetal cyclization [14].
Our purpose was to prepare all the twelve (3×4) possible stereoisomers of the
regioisomers 1–3 in enantiomerically pure form. So, we had to find a synthetic
approach different from those reported in the literature. We envisaged tetrahydropy-
ranols of type 4 as key intermediates, to be eventually obtained in all the eight possible
stereoisomeric forms. As a matter of fact, previous experience on dehydration of irol
derivatives [15] had taught us that the outcome of the dehydration of cyclohexanol
derivatives is highly influenced by the configuration of the OH group. The synthetic
path reported in Scheme 2 seemed be a good approach to obtain the single stereoisom-
ers of the monoacetates 5 as suitable acyclic precursors of 4.
Lipase PS mediated acetylation of the hydroxy ketone 6 gave, after 48 h, the acetyl
derivative (R)-7 in an enantiomeric excess (ee) of 98% (chiral HPLC analysis of the
corresponding alcohol). Prolonged enzyme-mediated acetylation of the unreacted alco-
hol gave, after 15 d, the enantiomer (ꢀ)-(S)-6 (ee=90%). The biocatalyzed kinetic res-
olution of 6 had been already reported by Nair and Joly [16][17], together with the
assignment of the absolute configuration. They described that, after a 28-h reaction
time, Candida rugosa lipase afforded (+)-(R)-7 (ee>96%) and (ꢀ)-(S)-6 (ee=50%).
Next, (R)-7 and (S)-6 were reacted separately with ‘b-metallyl magnesium chlo-
ride’4) in THF. The mixtures were then treated with Ac2O in pyridine, and submitted
to ozonolysis at ꢀ788 in CH2Cl2/MeOH. After quenching with NaBH4,
(1R,3RS,5RS)-5 and (1S,3RS,5RS)-5 were obtained, respectively, both as mixtures of
diastereoisomers.
4
)
Systematic name: (chloro)(2-methylprop-2-enyl)magnesium.

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Scheme 2
i) Lipase PS, t-BuOMe, vinyl acetate. ii) b-Metallyl magnesium chloride4); 78%. iii) Ac2O, pyridine;
89%. iv) 1. O3, CH2Cl2/MeOH 2 :1; 2. NaBH4; 76%.
As shown in Scheme 3, we found that treatment of (1R,3RS,5RS)-5 with lipase PS in
t-BuOMe in the presence of vinyl acetate affords a 1:1 mixture of the two diastereoi-
someric diacetates (1R,3RS,5S)-10. The absolute configuration at C(5) was first tenta-
tively assigned on the basis of the known preference of lipase PS for the acetylation of
stereogenic centers of (R)-configuration. This assignment was confirmed by the analy-
sis of the relative configuration of the corresponding tetrahydropyranols. Prolonged
lipase PS treatment of the survived alcohol gave a 1:1 mixture of the monoacetates
(1R,3RS,5S)-5.
Scheme 3
i) Lipase PS, t-BuOMe, vinyl acetate; purification by column chromatography. ii) Lipase PS, THF/
H2O (pH 7.8).
When the mixture of diacetates 10 was submitted to lipase PS mediated saponifica-
tion in THF/H2O (pH 7.8), a 1:1 mixture of the two monoacetates (1R,3R,5R)- and
(1R,3S,5R)-5 was obtained. The combination of the two enantioselective lipase-cata-
lyzed acetylations with the regioselective enzyme-mediated hydrolysis, thus, allowed

Helvetica Chimica Acta – Vol. 89 (2006)
181
us to separate the stereoisomers of (1R)-5, with opposite relative configurations at C(1)
and C(5).
Next, the two mixtures of monoacetates were submitted separately to ring closure
by treatment with methanesulfonyl chloride (MsCl) in pyridine, followed by exposure
to MeONa in MeOH (Scheme 4). The 1:1 mixture of (1R,3RS,5R)-5 gave (2S,4S,6R)-
and (2S,4R,6R)-4, which could be separated by column chromatography. Both the ster-
eoisomers showed a trans arrangement of the substituents at C(2) and C(6). The first
eluted diastereoisomer, i.e., (2S,4S,6R)-4, was found to have the Ph group in axial
and the Me group in equatorial position, respectively (d(H) 5.05 (dd, J=3.7, 9.6 Hz,
HꢀC(6)); 4.25 (dquint., J=3.3, 6.4 Hz, HꢀC(2))). The OH group was assumed to be
in axial position in both stereoisomers, on the basis of the outcome of the subsequent
dehydration steps.
Scheme 4
i) 1. MeSO2Cl, pyridine; 2. MeONa in MeOH. ii) Purification by column chromatography. iii) POCl3,
pyridine.
As shown in Scheme 5, the 1:1 mixture of (1R,3RS,5S)-5 gave (2R,4R,6R)-4 and
(2R,4S,6R)-4, which could be separated by column chromatography. Both the stereo-
isomers showed a cis-diequatorial arrangement of the substituents at C(2) and C(6).
The 1H-NMR spectrum of the first eluted diastereoisomer showed the following typical
resonances: d(H) 4.76 (dd, J=2.4, 11.5 Hz, HꢀC(6)) and 4.00 (ddq, J=11.5, 6.2, 2.3 Hz,
HꢀC(2)); the second eluted one gave rise to signals at 4.40 (dd, J=12.0, 2.3 Hz, Hꢀ
C(6)) and 3.68 (ddq, J=12.0, 6.1, 2.3 Hz, HꢀC(2)). The OH group was assumed to
be in axial position in the first eluted compound, and in equatorial position in the sec-
ond one, in accord with reference [6].

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Scheme 5
i) 1. MeSO2Cl, pyridine; 2. MeONa in MeOH. ii) Purification by column chromatography. iii) POCl3,
pyridine.
The cyclization of the monoacetates 5 proceeded under inversion of configuration
at C(5). The relative configuration at C(2) and C(6) of the resulting tetrahydropyranols
4 was, thus, in accord with that of the starting monoacetates, assigned on the basis of the
known preference of lipase PS for (R)-configured stereogenic centers.
The dehydration of these four diastereoisomeric tetrahydropyranols was performed
by treatment with POCl3 in pyridine. We had already employed this reaction in the
chemistry of irol derivatives [15]. We observed that this transformation requires precise
stereochemical requisites, typical of an E2-type elimination, i.e., an antiperiplanar
arrangement of the H-atom and the leaving group. In such cyclohexane derivatives,
this steric condition is best satisfied when the H-atom and, in this case, the phosphate
ester are in a trans-diaxial relation. Dehydration of (2S,4S,6R)-, (2S,4R,6R)-, and
(2R,4R,6R)-4, showing the OH group in axial position, gave mainly the endocyclic ole-
fins. Column-chromatographic (CC) purification of these mixtures allowed us to isolate
the following dihydropyran products (Schemes 4 and 5): (2S,6R)-2 (98% pure, ee 98%);
(2R,6S)-3 (99% pure, ee 98%); a sample enriched in (2S,6R)-1 (39% pure, ee 98%);
(2R,6R)-2 (94% pure, ee 98%); (2R,6R)-3 (97% pure, ee 98%).
The reaction of (2R,4S,6R)-4 with the equatorial OH group afforded, exclusively,
the exo-olefinic pyran (2R,6R)-1 (99% pure, ee 98%). In this substrate, the H-atom
of the Me group may satisfy an antiperiplanar arrangement with respect to the equato-
rial OH group.

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As for the series prepared starting from (S)-6, the enzymatic acetylation of the mix-
ture of the four stereoisomers (1S,3RS,5RS)-5 was too slow to allow practical applica-
tion. Ring closure and CC purification gave a mixture of the three tetrahydropyranols
(2S,4S,6S)-4 and (2R,4RS,6S)-4 as the first eluted product, while the fourth one,
(2S,4R,6S)-4, was obtained as a pure crystalline compound (Scheme 6).
Scheme 6
i) 1. MeSO2Cl, pyridine; 2. MeONa in MeOH. ii) Purification by column chromatography. iii) POCl3,
pyridine.
The dehydration reaction of the mixture of (2S,4S,6S)-4 and (2R,4RS,6S)-4 required
a very careful and laborious CC purification, which gave rise to the following com-
pounds: (2R,6S)-2 (92% pure, ee 90%); (2S,6R)-3 (94% pure, ee 90%); a sample
enriched in (2R,6S)-1 (33% pure, ee 90%); (2S,6S)-2 (93% pure, ee 90%); (2S,6S)-3
(94% pure, ee 90%). Finally, treatment of (2S,4R,6S)-4 with POCl3 and pyridine gave
the corresponding exo compound (2S,6S)-1 (97% pure, ee 90%).
2. Odor Evaluation. All the stereoisomers of compounds 1–3 were submitted to
odor evaluation by skillful perfumers (Givaudan Schweiz AG). The following odor-
descriptions resulted:

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• (2S,6R)-trans-1 (39.5%): Green, Rose Oxide like, fruity, orange-type, and somewhat
dusty odor. Dry down weak, green, fruity.
• (2R,6S)-trans-1 (24.7%): Harsh, green, technical, pyrazine-type, vegetal odor, with
acetic, Rose Oxide type, floral-rosy facets. Dry down green, fruity, and rosy.
• (2R,6R)-cis-1: Weak, green, agrestic, and herbaceous odor, with a slightly fruity side.
Dry down very weak green, fruity.
• (2S,6S)-cis-1: Weak, fruity-floral, mushroom-like odor. Dry down very weak, fruity-
floral, somewhat technical.
• (2S,6R)-trans-2: Green, petit-grain and orange flower-type pleasant odor, with aspects
of neroli oil. Dry down linear, but more herbal, buccoxime-like.
• (2R,6S)-trans-2: Green, floral odor, with slightly wine- and food-like nuances, and
somewhat oily, technical aspects. Dry down linear, weak, green, vegetal.
• (2R,6S)-trans-3: Green, metallic, Rose Oxide note, stronger than (2S,6R)-trans-2 and
(2R,6R)-cis-2. Dry down green, fruity, buccoxime-like. This compound is the most
substantive of the series of enantiomers obtained from (R)-7.
• (2S,6R)-trans-3: Strong, green-fruity, fresh, but also somewhat harsh-technical odor.
Dry down fruity, Rose Oxide like, with a sweet rosy touch. This compound is the stron-
gest of the series of enantiomers prepared from (S)-6.
• (2R,6R)-cis-2: Green, metallic, Rose Oxide like odor, with fruity, slightly earthy, and
potato-like aspects. Dry down weak, green, fruity. This compound is weaker and
less-substantive than (2R,6S)-trans-3.
• (2S,6S)-cis-2: Rather weak, sharp, green, Rose Oxide like, stem odor, with a slightly
fruity and acetic tonality. Dry down very weak, slightly green.
• (2R,6R)-cis-3: Fruity, green, metallic odor. Dry down green fruity.
• (2S,6S)-cis-3: Strong, floral-green Rose Oxide odor, with a metallic inflection and a
typical rose tonality. Dry down linear, Rose Oxide like, floral, rosy.
Conclusions. – This careful work concerning the synthesis and odor evaluation of all
the possible stereoisomers of Pelargene highlights the importance of stereochemistry.
Cis-1 is the main component of the commercial Pelargene mixture. Both enantiomers
of 1 were found to have weak, not interesting odor profiles. Similarly, the enantiomers
of trans-1, which are not present in the commercial mixture, and which were obtained as
by-products in our dehydration reaction, are of no value from an odor point of view.
Trans-2 and trans-3 are present only in traces in commercial Pelargene. (2S,6R)-
trans-2 shows a very nice petit-grain and neroli odor not found in its enantiomer.
Both the enantiomers of trans-3 are very substantive. (2R,6S)-trans-3 has been assessed
to be much more interesting than its enantiomer.
Cis-2 and cis-3 are present in commercial Pelargene in 1.7 and 17%, respectively.
Both the enantiomers of cis-2 are rather weak, with no interesting odor. The (2S,6S)-
enantiomer of cis-3 is of great value for its rosy odor, while (2R,6R)-cis-3 has a fruity
and metallic odor.
(2S,6R)-trans-2, (2R,6S)-trans-3, and (2S,6S)-cis-3 are the most-valuable compo-
nents of Pelargene, although they represent just a very small percentage of the whole
commercial mixture.
From a synthetic point of view, our work shows the great versatility of lipase PS in
the enantioselective acetylation of hydroxy ketones such as 6. Stereoselective acetyla-

Helvetica Chimica Acta – Vol. 89 (2006)
185
tion of the monoacetate (1R,3RS,5RS)-5 allowed us to separate the two (1R,5S)-diaster-
eoisomers from the (1R,5R)-isomers. Chemoselective saponification in 5-position of
the acetate gave us the chance to recover the monoacetate, which can be used for
the desired ring closure. Biocatalysis, thus, has proven, once again, to be an efficient
tool for the selective synthesis of stereoisomers.
We would like to thank Dr. Philip Kraft and Mr. Jean Jacques Rouge (Givaudan Schweiz AG, Fra-
grance Research, Switzerland) for the odor descriptions. COFIN–Murst is acknowledged for financial
support.
Experimental Part
1. General. Lipase PS Burkholderia cepacia (Amano Pharmaceuticals Co., Japan) was employed in
this work. 4-Hydroxy-4-phenylbutan-2-one (6) was prepared according to [18]. TLC: Merck Kieselgel
60 F254 plates. All the column-chromatographic (CC) separations were carried out on Merck silica gel.
Chiral HPLC: Chiralcel OD column (Daicel, Japan), Merck-Hitachi L-6200 apparatus, with UV detector
(254 nm), elution with hexane/i-PrOH 95 :5 at 0.6 ml/min (tR 26.1 and 28.2 min for (S)- and (R)-6, resp.).
Optical rotations: Dr. Kernchen Propol digital automatic polarimeter. 1H- and 13C-NMR Spectra: Bruker
AC-250 spectrometer; in CDCl3 soln. at r.t., unless otherwise stated; chemical shifts d in ppm rel. to inter-
nal Me4Si, J in Hz. 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 (1 min)/60 !1508 at 68/min, 1508 (1 min),
150 !2808 at 128/min, 2808 (5 min). Elemental analyses: Carlo Erba 1106 analyzer.
2. (R)-3-Oxo-1-phenylbutyl Acetate ((R)-7) and (S)-4-Hydroxy-4-phenylbutan-2-one ((S)-6). A soln.
of rac-6 (70.0 g, 0.43 mol) in t-BuOMe (600 ml) was treated with Lipase PS (35 g) in the presence of vinyl
acetate (80 ml). After 48 h, the mixture was filtered, and purified by CC (SiO2; hexane/AcOEt 9 :1) to
afford (R)-7 (27.5 g, 31%). Prolonged enzyme-mediated acetylation of the unreacted alcohol gave,
after 15 d, (S)-6 (19.0 g, 27%).
Data of (R)-7. Chemical purity: 98% (by GC/MS; tR 16.99); 98% ee (chiral HPLC of the correspond-
1
ing alcohol). M.p. 43–448. [a]D =+64.7 (c=1.05, CHCl3) (lit. [a]D =+64.6 (c=0.71, CHCl3) [17]). H-
NMR [17]: 7.40–7.20 (m, Ph); 6.16 (dd, J=8.6, 4.8, HꢀC(1)); 3.09 (dd, J=16.6, 8.6, HꢀC(2)); 2.78
(dd, J=16.6, 4.8, HꢀC(2)); 2.11 (s, Me(4)); 2.00 (s, Ac). 13C-NMR [17]: 204.6; 169.6; 139.7; 128.4;
128.0; 126.1; 71.4; 49.5; 30.1; 20.8. GC/MS: 163 (91, [Mꢀ43]+), 145 (45), 131 (54), 105 (100), 43 (86).
Data of (S)-6. Chemical purity: 97% (by GC/MS; tR 14.26); 90% ee (chiral HPLC). [a]D =ꢀ64.8
(c=1.1, CHCl3) (lit. [a]D for (R)-6: =ꢀ36.1 (50% ee; c=1.7, CHCl3) [17]; +60.0 (83% ee; c=0.67,
CHCl3) [19]). 1H-NMR [17][19]: 7.40–7.20 (m, Ph); 5.18 (m, HꢀC(4)); 2.86 (dd, J=17.0, 8.6, Hꢀ
C(3)); 2.75 (dd, J=17.0, 3.3, HꢀC(3)); 2.11 (s, MeCO). GC/MS: 164 (13, M+), 146 (27), 106 (100), 77
(100).
3. (1R,3RS)-3,5-Dimethyl-1-phenylhex-5-ene-1,3-diol ((1R,3RS)-8). b-Metallyl chloride (=3-chloro-
2-methylprop-1-ene; 29.2 g, 0.325 mol) and (R)-7 (27.0 g, 0.13 mol) were added simultaneously under N2
to a suspension of Mg (9.60 g, 0.400 mol) in THF (500 ml), where the Grignard formation had already
been started by addition of a few drops of b-metallyl chloride. The mixture was poured into a soln. of
sat. aq. NH4Cl at 08, and extracted with Et2O. The org. phase was dried (Na2SO4) and evaporated to
afford, after purification by CC (SiO2; hexane/AcOEt 9 :1), a 1:1 mixture of the two diastereoisomers
(1R,3RS)-8 (22.3 g, 78%). Chemical purity: 96% (by GC/MS; tR 21.58). 1H-NMR (diastereoisomer mix-
ture): 7.50–7.10 (m, Ph); 5.12 (dd, J=7.4, 2.1, HꢀC(1) of one isomer); 5.08 (dd, J=7.6, 1.9, HꢀC(1) of
one isomer); 4.98, 4.96 (2m, HꢀC(6)); 4.82, 4.73 (2 br. s, HꢀC(6)); 2.59, 2.33 (2d, J=13.3 each, HꢀC(4));
2.1–1.6 (m, 3 H of each isomer); 1.87, 1.84 (2s, Me(6)); 1.42, 1.23 (2s, MeꢀC(3)). GC/MS: 202 (3,
[Mꢀ18]+), 187 (6), 165 (10), 147 (88), 107 (100). Anal. calc. for C14H20O2 (220.31): C 76.33, H 9.15;
found: C 76.47, H 9.07.
4. (1S,3RS)-8. b-Metallyl chloride (25.8 g, 0.287 mol) and (S)-6 (18.8 g, 0.114 mol) were added simul-
taneously under N2 to a suspension of Mg (8.16 g, 0.310 mol) in THF, where the Grignard formation had
already been started by addition of a few drops of b-metallyl chloride. The mixture was worked up and

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Helvetica Chimica Acta – Vol. 89 (2006)
purified as above to afford a 1:1 mixture of the two diastereoisomers (18.8 g, 75%). Chemical purity:
95% (by GC/MS; tR =21.58). The NMR and GC/MS data were in accord with those of the enantiomers.
Anal. calc. for C14H20O2 (220.31): C 76.33, H 9.15; found: C 76.26, H 9.24.
5. (1R,3RS)-3-Hydroxy-3,5-dimethyl-1-phenylhex-5-enyl Acetate ((1R,3RS)-9). The 1:1 mixture of
(1R,3RS)-8 (22.0 g, 0.10 mol) was treated with Ac2O (50 ml) in pyridine (50 ml). After usual workup, a
1:1 diastereoisomer mixture of (1R,3RS)-9 was obtained (23.3 g, 89%). Chemical purity: 98% (by
1
GC/MS; tR 22.01 and 22.07). H-NMR (diastereoisomer mixture): 7.50–7.10 (m, Ph); 6.07 (dd, J=7.1,
3.6, HꢀC(1) of one isomer); 6.05 (dd, J=7.3, 3.6, HꢀC(1) of one isomer); 4.93 (m, HꢀC(6) of one iso-
mer); 4.77 (br. s, HꢀC(6) of one isomer); 2.35–2.17 (m, 3 H of each isomer); 2.07, 2.05 (2s, AcO);
1.99–1.86 (m, 1 H of each isomer); 1.85, 1.84 (2s, Me(6)); 1.26, 1.25 (2s, MeꢀC(3)). GC/MS (isomer 1;
tR 22.01): 219 (1, [Mꢀ43]+), 147 (100), 107 (15). GC/MS (isomer 2; tR 22.07): 219 (0.5, [Mꢀ43]+), 147
(100), 107 (20). Anal. calc. for C16H22O3 (262.35): C 73.25, H 8.45; found: C 73.16, H 8.51.
6. (1S,3RS)-9. The 1:1 mixture of (1S,3RS)-8 (18.5 g, 0.084 mol) was treated with Ac2O (30 ml) in
pyridine (30 ml). After usual workup, a 1:1 diastereoisomer mixture of (1S,3RS)-9 was obtained (20.0
g, 91%). Chemical purity: 94% (by GC/MS; tR =22.01 and 22.07). The NMR and GC/MS data were in
accord with those of the enantiomers. Anal. calc. for C16H22O3 (262.35): C 73.25, H 8.45; found: C
73.32, H 8.53.
7. (1R)-3,5-Dihydroxy-3-methyl-1-phenylhexyl Acetate ((1R,3RS,5RS)-5). A soln. of (1R,3RS)-9
(23.1 g, 0.088 mol) in CH2Cl2/MeOH 2 :1 (500 ml) was treated with O3 at ꢀ788. The mixture was
quenched with NaBH4 (10.0 g, 0.264 mol), poured into H2O, and extracted with CH2Cl2. The org.
phase was dried (Na2SO4) and evaporated to give a mixture of the four possible diastereoisomers of
(1R)-5 (17.8 g, 76%). Chemical purity: 96% (by GC/MS; tR 23.33). 1H-NMR (isomer mixture):
7.50–7.20 (m, Ph); 6.10–5.80 (m, HꢀC(1)); 4.35–4.15 (m, HꢀC(5)); 2.50–2.10 (m); 2.10–2.00 (s,
AcO); 1.99–1.35 (m); 1.35–1.10 (s, MeꢀC(3) and Me(6)). GC/MS: 248 (1, [Mꢀ18]+), 188 (22), 147
(205), 104 (100). Anal. calc. for C15H22O4 (266.34): C 67.65, H 8.33; found: C 67.71, H 8.26.
8. (1S,3RS,5RS)-5. A soln. of (1S,3RS)-9 (18.3 g, 0.070 mol) in CH2Cl2/MeOH 2 :1 (500 ml) was
treated with O3 at ꢀ788. The mixture was quenched with NaBH4 (7.96 g, 0.21 mol), poured into H2O,
and extracted with CH2Cl2. The org. phase was dried (Na2SO4) and evaporated to give a mixture of
the four possible diastereoisomers of (1S)-5 (13.9 g, 75%). Chemical purity: 93% (by GC/MS; tR
23.33). The NMR and GC/MS spectra were in accord with those of the enantiomers. Anal. calc. for
C15H22O4 (266.34): C 67.65, H 8.33; found: C 67.59, H 8.27.
9. (1R,3RS,5R)-3-Hydroxy-3-methyl-1-phenylhexane-1,5-diyl Diacetate ((1R,3RS,5R)-10). A soln. of
the mixture of the four diastereoisomers of (1R)-5 (17.5 g, 0.066 mol) in t-BuOMe (150 ml) was treated
with Lipase PS (10.0 g) in the presence of vinyl acetate (20 ml). After 10 d, the mixture was filtered, and
the products were separated by CC (SiO2; hexane/AcOEt 9 :1) to afford (1R,3RS,5R)-10 (8.94 g, 44%)
and (1R,3RS,5S)-5 (7.19 g, 41%), both as 1:1 mixtures of two diastereoisomers.
Data of (1R,3RS,5R)-10. Chemical purity: 98% (by GC/MS; tR 23.37 and 23.40). 1H-NMR (isomer
mixture): 7.40–7.25 (m, Ph); 6.01 (dd, J=5.9, 3.2, HꢀC(1) of one isomer); 5.99 (dd, J=5.8, 3.2, Hꢀ
C(1) of one isomer); 5.22–5.13 (m, HꢀC(5)); 2.35–2.15 (m, 1 H of each isomer); 2.05, 2.04 (2s, AcO);
1.98, 1.97 (2s, AcO); 2.00–1.50 (m, 3 H of each isomer); 1.26 (d, J=6.4, Me(6) of one isomer); 1.25
(d, J=6.1, Me(6) of one isomer); 1.24, 1.23 (2s, MeꢀC(3)). GC/MS (isomer 1; tR 23.30): 290 (1,
[Mꢀ18]+), 265 (1), 230 (1), 188 (10), 147 (20), 104 (100), 85 (50). GC/MS (isomer 2; tR 23.40): 290 (1,
[Mꢀ18]+), 265 (1), 230 (1), 188 (9), 147 (23), 104 (100), 85 (55). Anal. calc. for C17H24O5 (308.38): C
66.21, H 7.84; found: C 66.36, H 7.78.
1
Data of (1R,3RS,5S)-5. Chemical purity: 97% (by GC/MS; tR 23.33). H-NMR (isomer mixture):
7.40–7.25 (m, Ph); 6.02, 5.94 (2dd, J=9.0 and 3.9 each, HꢀC(1)); 4.35–4.20 (m, HꢀC(5)); 2.45, 2.21
(2dd, J=14.6 and 9.0 each, 1 H); 2.08, 2.07 (2s, AcO); 1.95, 1.93 (2dd, J=14.6 and 3.9 each, 1 H);
1.73–1.61 (m, 1 H of each isomer); 1.52, 1.47 (2dd, J=14.6, 2.0, 1 H of each isomer); 1.33, 1.31 (2s,
MeꢀC(3)); 1.19, 1.12 (2d, J=6.1 each, Me(6)). Anal. calc. for C15H22O4 (266.34): C 67.65, H 8.33;
found: C 67.56, H 8.25.
10. (1R,3RS,5R)-5. To a suspension of Lipase PS (5.0 g) in H2O (50 ml), a soln. of the diacetate (1R,
3RS,5R)-10 (8.70 g, 0.028 mol) in THF (5 ml) was added. The pH was kept at 7.8 by means of a pH-stat.
After 12 h, the mixture was extracted with AcOEt, the org. phase was dried (Na2SO4), and concentrated

Helvetica Chimica Acta – Vol. 89 (2006)
187
under reduced pressure to give (1R,3RS,5R)-5 (5.21 g, 70%) as a 1:1 mixture of two diastereoisomers.
1
Chemical purity: 99% (by GC/MS; tR 23.33). H-NMR (isomer mixture): 7.40–7.25 (m, Ph); 6.03, 5.98
(2dd, J=9.0, 3.8, HꢀC(1)); 4.40–4.20 (m, HꢀC(5)); 2.27, 2.24 (2dd, J=14.6 and 9.0 each, 1 H of each
isomer); 2.11, 1.90 (2dd, J=14.6 and 3.8 each, 1 H of each isomer); 2.06, 2.04 (2s, AcO); 1.73–1.61
(m, 3 H); 1.49 (dd, J=14.6, 2.0, 1 H); 1.35, 1.27 (2s, MeꢀC(3)); 1.20, 1.19 (2d, J=6.1, Me(6)). Anal.
calc. for C15H22O4 (266.34): C 67.65, H 8.33; found: C 67.55, H 8.41.
11. Cyclization of the Monoacetates 5. 11.1. General Procedure (GP 1). To a soln. of the appropriate
monoacetate 5 (5.0 g, 0.019 mol) in pyridine (20 ml) was added mesyl chloride (3.20 g, 0.028 mol) at 08.
The mixture was stirred at r.t. for 1 h, poured onto ice, extracted with AcOEt, dried (Na2SO4), and con-
centrated. The residue was dissolved in MeOH (20 ml), and a 4M soln. of MeONa in MeOH (6 ml) was
added. The mixture was stirred at r.t. for 1 h. After usual workup, the residue was purified by CC (SiO2;
hexane/AcOEt 95 :5).
11.2. (2S,4S,6R)- and (2S,4R,6R)-3,4,5,6-Tetrahydro-2,4-dimethyl-6-phenyl-2H-pyran-4-ol ((2S,4S,
6R)- and (2S,4R,6R)-4). Prepared according to GP 1 from (1R,3RS,5R)-5 (2 diastereoisomers; 5.0 g,
0.019 mol).
Data of (2S,4S,6R)-4. Yield: 1.21 g (31%). Chemical purity: 61% (by GC/MS; tR 18.07). [a]2D0 =+1.1
1
(c=0.90, CHCl3). H-NMR: 7.50–7.20 (m, Ph); 5.10 (dd, J=5.7, 3.0, HꢀC(6)); 4.04 (ddq, J=10.2, 6.4,
3.0, HꢀC(2)); 2.36 (ddd, J=14.0, 3.0, 1.9, HeqꢀC(5) or HeqꢀC(3)); 2.04 (dd, J=14.0, 6.4, HaxꢀC(5));
1.60 (ddd, J=14.0, 3.0, 1.9, HeqꢀC(3) or HeqꢀC(5)); 1.46 (dd, J=10.2, 14.0, HaxꢀC(3)); 1.29 (s, Meꢀ
C(4)); 1.25 (d, J=6.4, MeꢀC(2)). 13C-NMR: 141.3; 128.4; 126.8; 125.7; 71.7; 68.6; 63.5; 45.4; 39.9;
30.8; 21.0. GC/MS: 188 (51, [Mꢀ18]+), 173 (83), 104 (80), 58 (100).
Data of (2S,4R,6R)-4. Yield: 1.64 g (42%). Chemical purity: 90% (by GC/MS; tR 18.77).
[a]2D0 =+6.64 (c=1.2, CHCl3). 1H-NMR: 7.50–7.20 (m, Ph); 5.05 (dd, J=9.6, 3.7, HꢀC(6)); 4.25 (dquint.,
J=6.4, 3.3, HꢀC(2)); 1.95–1.80 (m, 2 H); 1.76 (dd, J=13.9, 9.6, HaxꢀC(5)); 1.58 (ddd, J=13.9, 3.3, 1.9,
HeqꢀC(5) or HeqꢀC(3)); 1.49 (d, J=6.4, MeꢀC(2)); 1.23 (s, MeꢀC(4)). 13C-NMR: 142.7; 128.2; 127.0;
125.9; 68.9; 68.4; 68.2; 45.2; 42.2; 31.7; 19.8. GC/MS: 188 (60, [Mꢀ18]+), 173 (95), 105 (100), 58 (90).
Anal. calc. for C13H18O2 (206.29): C 75.69, H 8.80; found: C 75.57, H 8.71.
11.3. (2S,4S,6R)- and (2S,4R,6R)-4. Prepared according to GP 1 from (1R,3RS,5S)-5 (diaster-
eoisomer mixture; 6.90 g, 0.026 mol).
Data of (2R,4R,6R)-4. Yield: 1.82 g (34%). Chemical purity: 83% (by GC/MS; tR 18.15).
1
[a]2D0 =+18.5 (c=1.02, CHCl3). H-NMR [6]: 7.50–7.20 (m, Ph); 4.76 (dd, J=11.5, 2.4, HꢀC(6)); 4.00
(ddq, J=11.5, 6.2, 2.3, HꢀC(2)); 1.75 (dt, J=13.6, 2.3, HeqꢀC(3) or HeqꢀC(5)); 1.61 (dt, J=13.6, 2.3,
HeqꢀC(5) or HeqꢀC(3)); 1.55 (dd, J=13.6, 11.5, HaxꢀC(3) or HaxꢀC(5)); 1.37 (dd, J=13.6, 11.5, Haxꢀ
C(5) or HaxꢀC(3)); 1.26 (s, MeꢀC(4)); 1.25 (d, J=6.0, MeꢀC(2)). 13C-NMR [6]: 142.8; 128.2; 127.1;
125.9; 74.9; 69.2; 68.7; 46.0; 45.7; 31.4; 21.6. GC/MS: 188 (84, [Mꢀ18]+), 173 (100), 107 (53), 105 (69),
58 (31).
Data of (2R,4S,6R)-4. Yield: 2.30 g (43%). Chemical purity: 97% (by GC/MS; tR 18.42). M.p.:
107–1098. [a]2D0 =+36.8 (c=0.87, CHCl3). H-NMR [6]: 7.50–7.20 (m, Ph); 4.40 (dd, J=12.0, 2.3, Hꢀ
1
C(6)); 3.68 (ddq, J=6.1, 2.3, 12.0, HꢀC(2)); 1.87 (dt, J=12.0, 2.3, HeqꢀC(3) or HeqꢀC(5)); 1.74 (dt,
J=12.0, 2.3, HeqꢀC(5) or HeqꢀC(3)); 1.65 (t, J=12.0, HaxꢀC(3) or HaxꢀC(5)); 1.40 (t, J=12.0, Haxꢀ
C(5) or HaxꢀC(3)); 1.43 (s, MeꢀC(4)); 1.29 (d, J=6.0, MeꢀC(2)). 13C-NMR [6]: 142.1; 128.2; 127.3;
125.9; 77.0; 71.3; 69.3; 47.8; 47.6; 25.8; 21.9. GC/MS: 188 (50, [Mꢀ18]+), 173 (78), 107 (91), 58 (100).
11.4. (2S,4S,6S)-, (2R,4RS,6S)-, and (2S,4R,6S)-4. Prepared according to GP 1 from (1S,3RS,5RS)-5
(four diastereoisomers; 13.7 g, 0.051 mol). A mixture of (2S,4S,6S)-4 (28%, GC/MS) and (2R,4RS,6S)-4
(72%, GC/MS) was eluted first (6.72 g, 64%), followed by (2S,4R,6S)-4 (single stereoisomer; 1.58 g,
15%).
Data of (2S,4R,6S)-4. Chemical purity: 97% (by GC/MS; tR 18.42). [a]2D0 =ꢀ34.1 (c=1.01, CHCl3).
M.p. 1098. The MS and NMR spectra were in accordance with those of the enantiomer.
12. Dehydration of Compounds 4. 12.1. General Procedure (GP 2). To a soln. of the pertinent starting
material 4 (1.60 g, 7.76 mmol) in pyridine (10 ml) was added POCl3 (1.54 g, 0.01 mol) at 08. The mixture
was stirred at r.t. for 1 h, then poured onto ice, extracted with AcOEt, dried (Na2SO4), and evaporated.
The residue was purified by CC (SiO2; hexane).

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12.2. (2S,6R)-3,4,5,6-Tetrahydro-2-methyl-4-methylidene-6-phenyl-2H-pyran ((2S,6R)-1), (2S,6R)-3,
6-Dihydro-2,4-dimethyl-6-phenyl-2H-pyran ((2S,6R)-2), and (2R,6S)-3,6-Dihydro-4,6-dimethyl-2-phen-
yl-2H-pyran ((2R,6S)-3). Prepared according to GP 2 from (2S,4S,6R)-4 (1.10 g) to afford (2S,6R)-1
(7%, GC/MS), (2S,6R)-2 (50%, GC/MS), and (2R,6S)-3 (43%, GC/MS). When prepared from (2S,4R,
6R)-4 (1.50 g) according to GP 2, (2S,6R)-1 (6%, GC), (2S,6R)-2 (22%, GC), and (2R,6S)-3 (72%,
GC) were obtained. The following anal. data refer to samples purified by CC (SiO2, hexane) and
bulb-to-bulb distillation.
Data of (2S,6R)-1. Sample: 0.105 g. Purity: 39% (by GC/MS; tR 15.42). 1H-NMR (main signals): 4.89
(br. s, 1 H of H2C=C); 4.81 (m, HꢀC(6), 1 H of H2C=C); 4.11 (m, HꢀC(2)); 1.24 (d, J=6.1, MeꢀC(2)).
GC/MS: 188 (5, M+), 144 (65), 129 (100), 67 (92).
Data of (2S,6R)-2. Sample: 0.220 g. Purity: 98% (by GC/MS; tR 15.46). [a]2D0 =+157.3 (c=0.75,
1
CHCl3). H-NMR: 7.45–7.20 (m, Ph); 5.70 (m, HꢀC(5)); 5.23 (m, HꢀC(6)); 3.70 (m, HꢀC(2)); 1.90
(m, CH2(3)); 1.80 (s, MeꢀC(4)); 1.19 (d, J=6.3, MeꢀC(2)). 13C-NMR: 142.6; 133.8; 128.8; 128.4;
127.9; 121.7; 74.6; 64.6; 37.9; 23.7; 21.7. GC/MS: 188 (31, M+), 173 (74), 129 (70), 105 (100), 77 (52).
Anal. calc. for C13H16O (188.27): C 82.94, H 8.57; found: C 82.85, H 8.50.
Data of (2R,6S)-3. Sample: 0.310 g. Purity: 99% (by GC/MS; tR 15.86). [a]2D0 =+157.8 (c=0.85,
1
CHCl3). H-NMR [6]: 7.55–7.20 (m, Ph); 5.47 (m, HꢀC(5)); 4.75 (dd, J=9.0, 4.0, HꢀC(2)); 4.44 (br.
s, HꢀC(6)); 2.27 (m, HꢀC(3)); 2.11 (m, HꢀC(3)); 1.77 (s, MeꢀC(4)); 1.30 (d, J=6.3, MeꢀC(6)). 13C-
NMR: 142.5; 131.2; 128.3; 127.3; 126.3; 124.7; 69.7; 69.2; 36.6; 22.9; 20.2. GC/MS: 188 (8, M+), 173
(16), 145 (33), 91 (67), 82 (83), 67 (100).
12.3. (2R,6R)-1, (2R,6R)-2, and (2R,6R)-3. Prepared according to GP 2 from (2R,4R,6R)-4 (1.70 g,
8.25 mmol) to afford (2R,6R)-1 (6%, GC/MS), (2R,6R)-2 (26%, GC/MS), (2R,6R)-3 (48%, GC/MS),
trans isomers (2%, GC/MS). When (2R,4S,6R)-4 (2.20 g, 0.197 mol) was used as starting material, (2R,
6R)-1 was obtained. The following anal. data refer to samples purified by CC (SiO2, hexane) and
bulb-to-bulb distillation.
Data of (2R,6R)-1. Sample: 1.48 g (74%). Purity: 99% (by GC/MS; tR 14.77). [a]2D0 =ꢀ11.5 (c=1.10,
1
CHCl3). H-NMR [6][14]: 7.50–7.20 (m, Ph); 4.80 (m, CH2=C); 4.34 (dd, J=11.3, 2.5, HꢀC(6)); 3.60
(ddq, J=11.1, 6.3, 2.3, HꢀC(6)); 2.44 (m, 1 H); 2.37–2.17 (m, 2 H); 2.05 (m, 1 H); 1.32 (d, J=6.1,
MeꢀC(2)). 13C-NMR [6][14]: 144.8; 142.5; 128.3; 127.4; 125.9; 108.5; 80.4; 74.9; 42.6; 42.3; 21.9. GC/
MS: 188 (14, M+), 144 (86), 129 (93), 107 (78), 67 (100).
Data of (2R,6R)-2. Sample: 0.240 g (15%). Purity: 94% (by GC/MS; tR 15.29). [a]2D0 =+68.2
(c=0.90, CHCl3). 1H-NMR: 7.50–7.20 (m, Ph); 5.44 (br. s, HꢀC(5); 5.12 (br. s, HꢀC(6)); 3.87 (m,
HꢀC(2)); 2.35–1.80 (m, 2 H); 1.74 (s, MeꢀC(4)); 1.32 (d, J=6.2, MeꢀC(2)). 13C-NMR: 142.9; 132.8;
128.6; 127.7; 126.5; 124.3; 71.1; 64.5; 38.2; 23.5; 22.3. GC/MS: 188 (25, M+), 173 (60), 145 (12), 129
(61), 105 (100), 77 (65). Anal. calc. for C13H16O (188.27): C 82.94, H 8.57; found: C 82.86, H 8.65.
Data of (2R,6R)-3. Sample: 0.379 g (24%). Purity: 97% (by GC/MS; tR 15.42). [a]2D0 =+90.65
(c=0.74, CHCl3). 1H-NMR [6]: 7.50–7.20 (m, Ph); 5.39 (m, HꢀC(5)); 4.57 (dd, J=3.6, 10.6, HꢀC(2));
4.36 (m, HꢀC(6)); 2.35–1.90 (m, 2 H); 1.73 (br. s, MeꢀC(4)); 1.29 (d, J=6.6, MeꢀC(6)). 13C-NMR
[6]: 142.8; 131.9; 128.3; 127.3; 125.9; 125.2; 76.0; 71.6; 37.7; 22.8; 21.6. GC/MS: 188 (5, M+), 173 (11),
145 (22), 82 (94), 67 (100).
12.4. (2S,6S)-2, (2S,6S)-3, (2R,6S)-1, (2R,6S)-2, and (2S,6R)-3. Prepared according to GP 2 from a
mixture (6.50 g, 0.031 mol) of the three isomers (2S,4S,6S)-4 (28%, GC/MS) and (2R,4RS,6S)-4 (72%,
GC/MS). Yields (by GC/MS): (2S,6S)-1 (2%), (2S,6S)-2 (10.1%), (2S,6S)-3 and (2R,6S)-1 (22.0%),
(2R,6S)-2 (35.4%), (2S,6R)-3 (30.5%). The following anal. data refer to samples purified by CC (SiO2;
hexane) and bulb-to-bulb distillation.
Data of (2S,6S)-2. Sample: 0.280 g (4.8%). Purity: 93% (by GC/MS; tR 15.29). [a]2D0 =ꢀ60.4 (c=1.05,
CHCl3). The MS and NMR data were in agreement with those of the enantiomer. Anal. calc. for C13H16O
(188.27): C 82.94, H 8.57; found: C 82.84, H 8.49.
Data of (2S,6S)-3. Sample: 0.210 g (3.6%). Purity: 94% (by GC/MS; tR 15.42). [a]2D0 =ꢀ79.8 (c=0.80,
CHCl3). The MS and NMR data were in agreement with those of the enantiomer.
Data of (2R,6S)-1. Sample: 0.170 g (2.9%). Purity: 33% (by GC/MS; tR 15.42).

Helvetica Chimica Acta – Vol. 89 (2006)
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Data of (2R,6S)-2. Sample: 0.305 g (5.2%). Purity: 92% (by GC/MS; tR 15.46). [a]2D0 =ꢀ138.8
(c=0.90, CHCl3). The MS and NMR data were in agreement with those of the enantiomer. Anal.
calc. for C13H16O (188.27): C 82.94, H 8.57; found: C 83.06, H 8.63.
Data of (2S,6R)-3. Sample: 0.310 g (5.3%). Purity: 94% (by GC/MS; tR 15.86). [a]2D0 =ꢀ136.1
(c=0.70, CHCl3). The MS and NMR data were in agreement with those of the enantiomer.
12.5. (2S,6S)-1. Prepared according to GP 2 from (2S,4R,6S)-4 (1.40 g, 6.79 mmol). Yield: 0.881 g
(69%). Purity: 97% (by GC/MS; tR 14.77). [a]2D0 =+9.9 (c=1.00, CHCl3).
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Received October 12, 2005