Enantioselective synthesis of each stereoisomer of the pyranoid linalool oxides: The linalool route

Article abstract of DOI:10.1016/S0957-4166(99)00359-6

Each of the four enantiomerically pure tetrahydropyran linalool oxides was prepared by separate enantioselective Sharpless dihydroxylation of (R)- or (S)-linalyl acetate with AD-mix-α or AD-mix-β, followed by a completely stereoselective N-phenylselenophthalimide cyclization of an intermediate allylic alcohol.

Full text of DOI:10.1016/S0957-4166(99)00359-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3547–3557
Enantioselective synthesis of each stereoisomer of the pyranoid
linalool oxides: the linalool route
Giovanni Vidari,a,∗ Anna Di Rosa,a Giuseppe Zanoni a and Carlo Bicchi b
aDipartimento di Chimica Organica, Università di Pavia, Via Taramelli 10, 27100 Pavia, Italy
bDipartimento di Scienza e Tecnologia del Farmaco, Via Giuria 9, 10125 Torino, Italy
Received 28 July 1999; accepted 13 August 1999
Abstract
Each of the four enantiomerically pure tetrahydropyranlinalool oxides was prepared by separate enantioselective
Sharpless dihydroxylation of (R)- or (S)-linalyl acetate with AD-mix-α or AD-mix-β, followed by a completely
stereoselective N-phenylselenophthalimide cyclization of an intermediate allylic alcohol. © 1999 Elsevier Science
Ltd. All rights reserved.
1. Introduction
A 2,2,6,6-tetrasubstituted pyran ring is an important structural fragment of many oxygenated natural
products and constitutes the basic skeleton of the four pyranoid linalool oxides 1 (3R,6R), 2 (3S,6R), 3
(3R,6S) and 4 (3S,6S). The latter compounds, as different mixtures of stereoisomers, have been found
as constituents of many tea, flower and fruit aromas, such as grapes and Carica papaya fruits.1,2 Even
though compounds 1–4 are usually minor constituents of these fragrances, they are considered to be
important contributors to a particular ‘note’ or ‘character’ of the scent.3 However, to our knowledge,
nobody has yet described the distinctive odour of each stereoisomer. In addition, they seem to have a
strong biological significance in certain pollination systems, acting as insect attractants.3
Recently, numerous syntheses of linalool oxides have been published, describing valuable selective
methods of the construction of substituted pyran rings which were later employed in the synthesis
∗
Corresponding author. Tel: 0039 0382 507322; fax: 0039 0382 507323; e-mail: vidari@chifis.unipv.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00359-6

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of more oxygenated natural products. Three general procedures4,5 were elaborated for assembling
linalool oxide-like tetrahydropyran structures: (i) by using a nucleophilic attack of a hydroxy group
to a double bond activated by coordination with a bromo,6,7 mercury8 or selenium reagent;9–13 (ii)
by controlled cyclization of an epoxyalcohol in acidic medium;10,14–16 and (iii) by an intramolecular
displacement of an allylic N-phenylcarbamate or carbonate moiety in the presence of a Lewis acid17
or a palladium catalyst,18 respectively. Unfortunately, these cyclizations generally proceed with poor
stereoselectivity, giving mixtures of cis- and trans-linalool oxides in almost equal amounts and often
together with the corresponding isomeric tetrahydrofuran oxides. A few years ago, we described16
a
highly enantioselective synthesis of compound 4 starting from (R)-(−)-linalool; however, our approach
suffered a serious drawback in terms of atom economy, since the vinyl group was first cleaved and then
reinstalled after the crucial cyclization step. We describe here a different stereocontrolled strategy that
allows the separate construction of each stereoisomeric linalool oxide, without sacrificing any carbon
atoms of the starting linalool.
2. Results and discussion
In our synthetic approach we envisioned a ∆5-alkenol derived from linalyl acetate as a key substrate for
the tetrahydropyran cyclization, anticipating that the 6-exo-cyclization mode would be largely favoured
over the 7-endo one. Scheme 1 shows the retrosynthesis for (3S,6R)-trans-linalool oxide 2 as a model
compound. Thus, assuming that the absolute configuration of compound 6 is retained in the cyclization
step, the starting enantiomer of linalyl acetate provides the C-6 stereocentre of the target compound while
the C-3 stereochemistry has to be installed by an asymmetric reaction. On the basis of previous results on
(R)-(−)-linalool, we expected the Sharpless asymmetric dihydroxylation (AD) of the distant double bond
of linalyl acetate to be highly regio- and stereoselective, thus affording an immediate precursor of olefin
6 of high enantiomeric purity and with a predictable absolute configuration at the secondary carbinol
stereocentre. In conclusion, all the four stereoisomers 1–4 should become easily accessible starting from
(R)- or (S)-linalyl acetate and using either AD-mix-α or AD-mix-β to install the other stereocentre.
Scheme 1. Retrosynthetic analysis
In the event, starting from (3R)-5, 98% ee, AD-mix-α gave the corresponding triol monoacetate,
(3S,6R)-7, in 92% yield and 95% de (1H NMR), while AD-mix-β afforded (3R,6R)-7 in 83% yield
and 97% de after flash column chromatography. In a similar fashion, (3S)-5, 96% ee,19 provided the
remaining two stereoisomers, (3S,6S)-7 and (3R,6S)-7, 95 and 95% de, respectively. In these asymmetric
reactions of 5, dihydroxylation of the 1,2-double bond was negligible. The absolute configurations of
the four products 7 were established via the Mosher’s esters and confirmed by the stereochemistry
of individual linalool oxide stereospecifically synthesized from each of them (vide infra). Compared
with the AD of the parent free alcohol linalool, we noticed the dihydroxylations of acetates 5 was
sluggish, requiring a higher osmium concentration (1 mol% OsO4) and higher temperature (4°C) to go
to completion. This was possibly due to the more pronounced steric and electron withdrawing effects of
the acetoxy group; moreover, the free OH group of linalool may assist the hydroxylation of the double
bond through precoordination with the osmium species. With all stereoisomers 8 in hand, we examined

G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
3549
different electrophilic species as effective promoters of the crucial cyclization step to pyran derivatives:
for this (3S,6R)-8, used as a model compound, was first converted with standard reactions into the desired
protected allylic diol (3R,6S)-6 in satisfactory overall yield (Scheme 2).
Scheme 2. (a) AD-mix-α; (b) (1-Naphthyl)NCO; (c) POCl3; (d) MeONa, MeOH; (e) N-PSP, cat. pyridinium p-toluene-
sulphonate; (f) Ph3SnH; (g) 10% MeONa, MeOH, reflux
Exposure of the latter compound to NBS in dry CH2Cl2 afforded, instead of the expected tetrahy-
dropyran product, the carbonate 12, arising from intramolecular cyclization of the carbamate group at
C-6 onto the 7,8-double bond of 6. Equally unsuccessful was the reaction of 6 with I2 in wet Et2O,
while I2 in MeCN returned unreacted starting material and 12% of a mixture of iodohydrin 13 and
iodotetrahydropyran 14.
Eventually, we resorted to electrophilic organoselenium reagents that are known to promote in-
tramolecular cyclization of unsaturated alcohols to rings of different sizes. Indeed, formation of a
tetrahydropyran ring by cyclization of a linalool derivative was achieved by Konstantinovic et al.;9
later, however, Urones10 cast serious doubts upon this claim. In the event, upon exposure to N-
(phenylseleno)phthalimide (N-PSP)13,20,21 and cat. p-TsOH in CH2Cl2, compound (3R,6S)-6 smoothly
afforded phenyl selenoethers (3S,6R)-10 as an inseparable mixture of diastereoisomers at C-2. These
compounds were accompanied by variable amounts of unreacted 6 and diselenides 15 (mixture of
stereoisomers), depending on the number of equivalents of N-PSP employed, reaction temperature and
extent of conversion of compound 6. Interestingly, we noticed the selenoetherification across the 7,8-
double bond of 6 was significantly slower than the ‘PhSeOH’ addition to the 1,2-olefin. Therefore, with
respect to the original procedure of Williard,13 in order to reduce the amount of the side product 15,
eventually we used only 1.2 equivalents of N-PSP, and the temperature of the reaction was kept below
5°C. Moreover, the reaction was stopped at ca. 60% conversion of 6. Under these optimized conditions,
tetrahydropyran 10 was produced in 45% yield based on recovered starting material. Other electrophilic
Se reagents, such as PhSeCl or PhSeSePh–H2O2, proved inferior promoters of the cyclization of (3R,6S)-
6 to the corresponding pyran. Though the tetrahydropyranyl yield with N-PSP was modest, the regio- and

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G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
stereoselectivities were, however, excellent. Actually, no oxepane product arising from the alternative
7-endo type cyclization was observed, while the ee and de of target compound 2 were higher than
20
98% (GC analysis on a β-cyclodextrine capillary column). The latter, [α]D +11.0 (CH2Cl2), was
eventually obtained from 10 by C–Se bond cleavage with Ph3SnH22 followed by hydrolysis of the 1-
1
naphthylcarbamate group in strong alkaline conditions. Compound 2 showed H and 13C NMR data
identical with the literature.14,17 Following an identical synthetic route, we converted each stereoisomeric
diacyl triol 8 (see above) into the corresponding linalool oxide: thus, (3R,6R)-8 gave pyran 1, (3R,6S)-
8 afforded 3 and (3S,6S)-8 led to 4. Each compound showed NMR data identical with those reported
in the literature,14,17 and de and ee >96%. In the Experimental, for the sake of clarity, we report only
one set of reactions carried out in the diastereomeric series started from (R)-5. Interestingly, we noticed
the cyclizations of (3R,6R)- and (3S,6S)-6 to be more sluggish than the corresponding (3R,6S)- and
(3S,6R)-6, respectively; in addition, starting material (3R,6R)- or (3S,6S)-6 rapidly degraded above 20%
Scheme 3.

G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
3551
conversion. The different reactivity of each diastereomer pair can be explained considering the chair-
like transition states leading to the cis- and trans-tetrahydropyran derivatives 10, respectively. The eight
transition states for the pair (3R,6R)- and (3S,6R)-6 are displayed in Scheme 3. The higher reactivity of
the former compound may be due to a higher stability of TSA and TSB compared to the other transition
states, owing to the smallest gauche and 1,3-diaxial interactions and the possible H-bond between the
axial carbamate substituent and the OH group.
3. Conclusions
This paper describes the first diastereo- and enantioselectively controlled synthesis of each of the four
stereoisomeric linalool oxides 1–4. The four compounds were produced in high ee and de. These results
illustrate the usefulness of the selenoetherification reaction of enantiomerically enriched ∆5-alkenols for
bridging two quaternary carbon atoms with an ether bond and pave the way for the preparation of a wide
array of 2,2,6,6-tetrasubstituted pyran derivatives of high enantiomeric excess.
Interestingly, a perfume expert asked to distinguish the scent of the four stereoisomers 1–4 perceived
no appreciable difference. Their odour was described as not intense, having a resin-like character with
overtones of citrus fruits, of flowers and balsam.
4. Experimental
4.1. General
Melting points were determined on a Fisher–Johns hot plate and are uncorrected. IR data (film)
1
were obtained on a Perkin–Elmer FT-IR Paragon 100 PC spectrometer. H NMR (300 MHz) and
13C NMR (75.47 MHz) spectra were recorded in CDCl3 solution unless otherwise indicated, using
a Bruker CXP 300 spectrometer. Chemical shifts are reported in δ units with Me4Si as the internal
standard; the abbreviations s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and b=broad are used
throughout. Coupling constants (J) are in hertz. The multiplicity (in parentheses) of each carbon atom
was determined by DEPT experiments. Mass spectra (direct inlet system) were recorded at 70 eV
(0.5 mA) with a Finnigan MAT 8222 instrument. All experiments were run in oven-dried glassware
under an argon atmosphere. Analytical TLC was carried out on 0.25 mm glass-supported silica gel
plates and visualization was effected with short-wavelength UV light (254 nm) or with 0.5% vanillin
solution in H2SO4:EtOH (4:1) followed by heating. Flash column chromatography was accomplished
with 230–400 mesh silica gel. De and ee were determined by GC using a Hewlett–Packard mod. 5890
instrument, equipped with an EASY DEX 6 β-CD capillary column (25 m×0.32 mm id and 0.25 µm
film thickness) (column A) and a Carlo Erba mod. 4160 instrument, equipped with a 30% 2,3-diethyl-6-
t-butyldimethylsilyi-β-CD on a PSO86 capillary column (25 m×0.25 mm id and 0.15 µm film thickness)
(column B). Optical activity was measured with a Perkin–Elmer 241 polarimeter. All commercial reagent
grade solvents were dried and degassed by standard techniques just before use. Yields are reported for
chromatographically and spectroscopically pure isolated compounds. Actually, isolated yields of volatile
compounds 1–4 were lowered by extensive losses occurring during evaporation of solutions containing
them. (R)-(−)-Linalool was a generous gift from R.C. Treatt & Co. Ltd., while (S)-(+)-linalool was
synthesized according to the literature.19

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4.2. (−)-(R)-3-Acetoxy-3,7-dimethylocta-1,6-diene (3R)-5
Ac2O (5.574 g, 54.6 mmol) and DMAP (146 mg, 1.2 mmol) were added to a solution of (−)-(R)-
linalool (6.000 g, 0.0384 mol) in pyridine (3.700 g, 0.0468 mmol). The mixture was stirred at 90°C
for 44 h, then quenched by adding MeOH and aqueous NaHSO4. The aqueous layer was extracted with
CH2Cl2 and the combined organic layers were dried over MgSO4, and taken to dryness. Separation of the
residue by column chromatography (gradient from hexane to 10% hexane:EtOAc) afforded (R)-linalyl
acetate (3R)-5 (7.489 g, 97% yield) as a colourless oil. [α]D20 −3.0 (c 1.0, CH2Cl2); IR 3057, 2984, 2937,
2876, 1734, 1653, 1442, 1368, 1240, 1168, 1096, 1043, 939, 926, 737, 704, 608 cm−1; 1H NMR δ 1.55
(s, 3H), 1.6 and 1.7 (s and s, 2×3H), 2.0 (s, 3H), 5.0–5.3 (m, 3H), 6.0 (m, 1H); EIMS C12H20O2 m/z:
136 (M−AcOH, 14), 121 (M−Me, 20), 107 (10), 93 (100), 80 (42), 71 (35), 69 (68), 55 (20), 43 (100),
41(58); CIMS (NH3) C12H20O2 m/z: 231 (M+NH4+NH3), 214 (M+NH4), 154 (M−AcOH+NH4). Anal.
calcd for C12H20O2: C, 73.43; H, 10.27. Found: C, 73.35; H, 10.32.
4.3. (3S,6R)-6-Acetoxy-2,6-dimethyloct-7-en-2,3-diol (3S,6R)-7
AD-mix-α (12.00 g) was added to a stirred 1:1 mixture of tBuOH:H2O (51 mL), and stirring was
continued at room temperature (25°C) until two bright yellow phases were obtained. MeSO2NH2 (484
mg, 5.08 mmol) was added, followed by linanyl acetate (R)-5 (1.000 g, 5.10 mmol) at 0°C. The
heterogeneous mixture was stirred vigorously at 4°C for 20 h, then quenched with solid Na2SO3; stirring
was continued for 30 min, until decoloration, allowing the mixture to warm to room temperature. CH2Cl2
was added and after separation of the layers the aqueous phase was further extracted with the same
organic solvent. The combined organic layers were treated with aq. 2 M KOH, dried over MgSO4 and
concentrated. The residue was purified by column chromatography on silica gel (hexane:AcOEt, 1:2) to
20
afford (3S,6R)-7 as a colourless oil (1.080 g, 92%, 95% de). [α]D −19.3 (c 0.6, CH2Cl2); IR 3418,
2975, 1734, 1644, 1371, 1255, 1170, 1075, 1021, 911, 733 cm−1; 1H NMR of major stereoisomer: δ 1.15
(s, 3H), 1.20 (s, 3H), 1.55 (s, 3H), 1.20–1.61 (m, 2H), 1.7–1.9 (m, 1H), 2.01 (s, 3H), 2.10–2.22 (m, 1H),
3.30 (br d, J=10, 1H), 5.10–5.20 (2H, ABX), 5.93 (1H, ABX); 13C NMR of major stereoisomer: δ 169.95
(s), 141.63 (d), 113.24 (t), 82.79 (s), 78.52 (d), 73.00 (s), 37.04 (t), 26.46 (q), 25.54 (t), 23.55 (q), 23.26
(q), 22.08 (q); CIMS (NH3) C12H22O4 m/z: 248 (M+NH4)+, 230 (M)+, 188 (M−AcOH+NH4 ). Anal.
+
calcd for C12H22O4: C, 62.58; H, 9.63. Found: C, 62.48; H, 9.70.
4.4. (3R,6R)-6-Acetoxy-2,6-dimethyloct-7-en-2,3-diol (3R,6R)-7
(R)-Linalyl acetate (2.000 g, 10.2 mmol) was submitted to AD-mix β (24.00 g) in the same conditions
as indicated in Section 4.3 to afford the diol (3R,6R)-7 as a colourless oil (1.957 g, 83.3% yield, 97% de).
20
[α]D −2.9 (c 1.4, CH2Cl2); IR 3422, 2975, 1734, 1644, 1369, 1264, 1160, 1075, 1021, 911, 733 cm−1;
1H NMR of major stereoisomer: δ 1.18 (s, 3H), 1.22 (s, 3H), 1.25–1.55 (m, 2H), 1.58 (s, 3H), 1.88–2.10
(m, 2H), 2.02 (s, 3H), 2.35 (br s, 1H), 3.32 (br d, J=10, 1H), 5.11–5.20 (2H, ABX), 5.95 (1H, ABX); 13
C
NMR of major stereoisomer: δ 169.87 (s), 141.24 (d), 113.23 (t), 82.85 (s), 78.37 (d), 72.87 (s), 36.90
(t), 26.32 (q), 25.45 (t), 23.63 (q), 23.12 (q), 21.98 (q); CIMS (NH3) C12H22O4 m/z: 248 (M+NH4)+, 230
(M)+, 188 (M−AcOH+NH4 ). Anal. calcd for C12H22O4: C, 62.58; H, 9.63. Found: C, 62.50; H, 9.68.
+

G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
3553
4.5. (3S,6R)-6-Acetoxy-3-(N-1-naphthyl)carbamoyloxy-2,6-dimethyloct-7-en-2-ol (3S,6R)-8
Dry pyridine (9.83 g, 124.3 mmol), followed by N-1-naphthylisocyanate (4.24 g, 25 mmol), was added
to a solution of (3S,6R)-7 (1.080 g, 4.69 mmol) in dry CH2Cl2 (30 mL) at 0°C under an argon atmosphere.
The mixture was stirred for 2.5 h at the same temperature then quenched with water; vigorous stirring was
continued for 30 min, to completely hydrolyse N-1-naphthylisocyanate in excess. The mixture was then
filtered through a Celite pad. After separation of the layers the aqueous phase was extracted with CH2Cl2.
The combined organic phases were treated with a saturated solution of NaHSO4, dried over MgSO4 and
concentrated. The residue was purified by column chromatography on silica gel (hexane:EtOAc, 3:2)
20
to afford (3S,6R)-8 (1.310 g, 70%). [α]D −13.4 (c 2.8, CH2Cl2); IR 3340, 2978, 2937, 1734, 1713,
1
1538, 1371, 1237, 1177, 1073, 1005, 793, 772 cm−1; H NMR δ 1.22 (s, 3H), 1.27 (s, 3H), 1.55 (s,
3H), 1.60–1.90 (m, 4H), 2.01 (s, 3H), 2.10 (br s, 1H, OH), 4.76 (br d, J=10, 1H), 5.10–5.20 (2H, ABX),
5.91 (1H, ABX), 7.15 (br s, 1H, NH), 7.40–7.98 (m, 7H); EIMS C23H29NO5 m/z: 399 (M+, 25), 339
(M−AcOH, 5), 187 (70), 169 (100), 143 (70), 115 (20), 109 (20), 81 (30), 71 (25), 57 (18), 43 (45);
HRMS m/z: 399.2051 (calcd for C23H29NO5: 399.2046).
4.6. (3R,6R)-6-Acetoxy-3-(N-1-naphthyl)carbamoyloxy-2,6-dimethyloct-7-en-2-ol (3R,6R)-8
Compound (3R,6R)-7 (1.687 g, 7.32 mmol) was submitted to the same conditions as indicated for (3S,
20
6R)-7 in Section 4.5 to afford after purification (3R,6R)-8 (2.107 g, 72% yield). [α]D +12.6 (c 1.9,
CH2Cl2); IR 3330, 3054, 2978, 2937, 1732, 1713, 1540, 1371, 1237, 1177, 1073, 1025, 1005, 793, 772
1
cm−1; H NMR δ 1.25 (s, 3H), 1.27 (s, 3H), 1.55 (s, 3H), 1.56–1.82 (m, 2H), 1.88–2.00 (m, 2H), 2.04
(s, 3H), 2.15 (br s, 1H), 4.76 (br d, J=10.5, 1H), 5.05–5.20 (2H, ABX), 5.93 (1H, ABX), 7.15 (br d, 1H,
NH), 7.40–7.98 (m, 7H); EIMS C23H29NO5 m/z: 399 (M+, 10), 339 (M−AcOH, 3), 187 (52), 169 (100),
143 (62), 115 (20), 109 (18), 81 (38), 71 (28), 59 (23), 57 (18), 43 (70); HRMS m/z: 399.2049 (calcd for
C23H29NO5: 399.2046).
4.7. (3S,6R)-6-Acetoxy-3-(N-1-naphthyl)carbamoyloxy-2,6-dimethylocta-1,7-diene (3S,6R)-9
POCl3 (4.384 g, 28.60 mmol) was slowly added via syringe to a stirred solution of (3S,6R)-8 (1.145
g, 2.87 mmol) in dry pyridine (10 mL) at 0°C under an argon atmosphere. The mixture was stirred at
room temperature for 1.5 h, then poured onto ice. After separation of two layers, the aqueous phase
was extracted with CH2Cl2. The combined organic layers were treated with aq. NaHSO4, aq. 5%
NaHCO3 and brine, then dried over MgSO4 and evaporated. The crude product was purified by column
20
chromatography on silica gel (hexane:AcOEt, 7:3 to 6:4) to afford pure (3S, 6R)-9 (0.71 g, 65%). [α]D
+6.1 (c 1.23, CH2Cl2); IR 3322, 3052, 2928, 1732, 1651, 1538, 1499, 1370, 1255, 1103, 1003, 791, 771
cm−1; 1H NMR δ 1.55 (s, 3H), 1.60–1.95 (4H), 1.76 (s, 3H), 2.04 (s, 3H), 4.92–5.22 (m, 5H), 5.94 (m,
1H, ABX), 7.01 (br s, 1H, NH), 7.41–7.98 (m, 7H); EIMS C23H27NO4 m/z: 381 (M+, 17), 187 (42), 169
(37), 143 (98), 135 (27), 115 (22), 107 (44), 93 (72), 79 (25), 71 (33), 55 (54), 43 (100). Anal. calcd for
C23H27NO4: C, 72.42; H, 7.13; N, 3.67. Found: C, 72.49; H, 7.21; N, 3.56.
4.8. (3R,6R)-6-Acetoxy-3-(N-1-naphthyl)carbamoyloxy-2,6-dimethylocta-1,7-diene (3R,6R)-9
Compound (3R,6R)-8 (1.532 g, 3.83 mmol) was submitted to the same conditions as indicated for (3S,
6R)-8 in Section 4.7 to afford after purification (3R,6R)-9 (0.876 g, 60%). [α]D20 −11.7 (c 3.60, CH2Cl2);
IR 3322, 3054, 2976, 1733, 1653, 1539, 1499, 1370, 1255, 1221, 1103, 1023,1003, 792, 771 cm−1; 1H

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G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
NMR δ 1.55 (s, 3H), 1.60–1.95 (4H), 1.75 (s, 3H), 2.04 (s, 3H), 4.95 (br s, 1H), 5.05 (br s, 1H), 5.10–5.20
(m, 3H), 5.93 (1H, ABX), 7.00 (br s, 1H, NH), 7.41–7.98 (m, 7H); EIMS C23H27NO4 m/z: 381 (M+, 21),
187 (43), 169 (40), 143 (100), 135 (26), 115 (22), 107 (44), 93 (69), 79 (23), 71 (21), 55 (40), 43 (77).
Anal. calcd for C23H27NO4: C, 72.42; H, 7.13; N, 3.67. Found: C, 72.51; H, 7.16; N, 3.59.
4.9. (3R,6S)-6-(N-1-Naphthyl)carbamoyloxy-3,7-dimethylocta-1,7-dien-3-ol (3R,6S)-6
To a solution of (3S,6R)-9 (485 mg, 1.27 mmol) in dry MeOH was added 10% MeONa in MeOH
(341 mg, 6.31 mmol of MeONa). The mixture was stirred at room temperature for 1 h under an argon
atmosphere. The reaction was quenched by adding water and the aqueous phase was extracted with
CH2Cl2. The combined organic layers were treated with a saturated solution of NH4Cl, dried over MgSO4
and concentrated. The residue was purified by column chromatography on silica gel (hexane:AcOEt, 7:3)
20
to afford (3R,6S)-6 (330 mg, 76.5%). [α]D +0.26 (c 0.50, CH2Cl2); IR 3450–3300, 3080, 3050, 2966,
1
2924, 1702, 1534, 1497, 1220, 1103, 1071, 1001, 791, 770 cm−1; H NMR δ 1.30 (s, 3H), 1.45–1.80
(4H), 1.76 (br s, 3H), 4.94 (br s, 1H), 5.03 (br s 1H), 5.08–5.27 (m, 3H), 5.89 (1H, ABX), 6.95 (br s, 1H,
NH), 7.40–7.90 (m, 7H); EIMS C21H25NO3 m/z: 339 (M+, 8), 187 (48), 169 (M+−AcOH, 14), 143 (100),
115 (21), 107 (21), 93 (30), 81 (16), 71 (27), 67 (20), 55 (16), 43 (32). Anal. calcd for C21H25NO3: C,
74.31; H, 7.42; N, 4.13. Found: C, 74.20; H, 7.49; N, 4.10.
4.10. (3R,6R)-6-(N-1-Naphthyl)carbamoyloxy-3,7-dimethylocta-1,7-dien-3-ol (3R,6R)-6
Compound (3R,6R)-9 (497 mg, 1.30 mmol) was submitted to the same conditions as indicated for
20
(3S,6R)-9 to afford (3R,6R)-6 (362 mg, 82%). [α]D −19.6 (c 1.00, CH2Cl2); IR 3450–3300, 2970,
1
2930, 1710, 1650, 1534, 1500, 1255, 1220, 1103, 1071, 1001, 920, 791, 772 cm−1; H NMR δ 1.30
(s, 3H), 1.50–1.80 (m, 4H), 1.72 (br s, 3H), 4.93 (br s, 1H), 5.02 (br s, 1H), 5.05–5.27 (m, 3H), 5.88
(1H, ABX), 7.02 (br s, 1H, NH), 7.40–7.90 (m, 7H); EIMS C21H25NO3 m/z: 339 (M+, 7), 187 (46), 169
(M+−AcOH, 13), 143 (100), 115 (20), 107 (23), 93 (32), 81 (18), 71 (30), 67 (21), 55 (32), 43 (49). Anal.
calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.36; H, 7.38; N, 4.04.
4.11. (2RS,3S,6R)-Tetrahydro-3-(N-1-naphthyl)carbamoyloxy-6-ethenyl-2-phenylselenylmethyl-2,6-
dimethyl-2H-pyran (2RS,3S,6R)-10
A catalytic amount of PPTS and N-PSP (362 mg, 1.20 mmol) was added at −78°C to a stirred solution
of (3R,6S)-6 (340 mg, 1.0 mmol) in CH2Cl2 under an argon atmosphere. The mixture was stirred at
−78°C for 2 h; then it was allowed to warm to 0°C and maintained at this temperature for 24 h. Stirring
was then continued at 5°C for 5 h. The mixture was then filtered and evaporated. The residue was purified
by column chromatography on silica gel (hexane:AcOEt, 7:3) to afford (2RS,3S,6R)-10 (165 mg, 42%
yield on the recovered starting material) and unreacted (3R,6S)-6 (70 mg). Compound (2 RS,3S,6R)-10:
[α]D20 +69.3 (c 0.2, CH2Cl2); IR 3422, 3053, 2983, 1730, 1532, 1495, 1209, 895, 704 cm−1; 1H NMR δ
1.20 (s, 3H), 1.40 (s, 3H), 1.70–2.10 (m, 4H), 3.00–3.30 (br m, 2H, CH2SePh), 4.90 (br s, 1H), 4.95–5.10
(2H, ABX), 5.95 (1H, ABX), 6.95 (br s, 1H, NH), 7.01–7.98 (m, 7H); EIMS C27H29NO3Se m/z: 491–499
(cluster Se), 324 (30), 188 (13), 169 (34), 155 (43), 137 (100), 115 (12), 95 (24), 93 (27), 81 (31), 79
(15), 67 (11), 55 (21), 43 (90).

G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
3555
4.12. (2RS,3R,6R)-Tetrahydro-3-(N-1-naphthyl)carbamoyloxy-6-ethenyl-2-phenylselenylmethyl-2,6-
dimethyl-2H-pyran (2RS,3R,6R)-10
In the case of (3R,6R)-6 (230 mg, 0.678 mmol), the mixture was stirred at −78°C for 2 h, at 0°C
for 45 h, and at 5°C for 24 h. Chromatographic separation afforded (2RS,3R,6R)-10 (30 mg, 40% yield
20
on the recovered starting material) and unreacted (3R,6R)-6 (187 mg). (2RS,3R,6R)-10, [α]D +9.3 (c
0.2, CH2Cl2); IR 3428, 3054, 2983, 1712, 1533, 1495, 1209, 909, 704 cm−1; 1H NMR δ 1.26 and 1.42
(2 br s, 2x3H), 1.60–2.20 (m, 4H), 3.00–3.60 (m, 2H), 4.70–5.20 (m, 3H), 5.95 (1H, ABX of minor
diastereisomer), 6.17 (1H, ABX of major diastereisomer), 6.90 (br s, 1H, NH), 7.10–7.98 (m, 7H); EIMS
C27H29NO3Se m/z: 491–499 (M+ cluster Se), 324 (66), 188 (30), 169 (60), 155 (67), 143 (30), 137 (91),
115 (21), 109 (17), 95 (42), 93 (47), 81 (58), 79 (21), 67 (20), 55 (39), 43 (100).
4.13. (3S,6R)-Tetrahydro-3-(N-1-naphthyl)carbamoyloxy-6-ethenyl-2,2,6-trimethyl-2H-pyran
(3S,6R)-11
Ph3SnH (211 mg, 0.6 mmol) was added to a refluxing stirred solution of (2RS,3S,6R)-10 (100 mg,
0.2 mmol) in dry toluene (2 mL) under an argon atmosphere. The mixture was refluxed and stirred
for 24 h, then allowed to cool to room temperature. After evaporation of toluene, the residue was
dissolved in MeCN. The solution was then filtered and extracted five times with hexane to remove tin
compounds. MeCN was evaporated and the residue was purified by RP 18 column chromatography
20
(from MeOH:H2O, 7:3, to 100% MeOH) to afford (3S,6R)-11 (42 mg, 61% yield). [α]D +13.9 (c 0.9,
1
CH2Cl2). IR 3315, 2966, 2929, 1706, 1534, 1497, 1345, 1216, 1084, 792, 770, 665 cm−1; H NMR δ
1.25 (br s, 6H), 1.30 (br s, 3H), 1.88 (m, 2H), 2.12 (m, 2H), 4.75 (br s, 1H), 4.95–5.11 (2H, ABX),
5.98 (1H, ABX), 7.05 (br s, 1H, NH), 7.45–7.95 (m, 7H); HRMS m/z: 339.1829 (calcd for C21H25NO3:
339.1834).
4.14. (3R,6R)-Tetrahydro-3-(N-1-naphthyl)carbamoyloxy-6-ethenyl-2,2,6-trimethyl-2H-pyran
(3R,6R)-11
Compound (2RS,3R,6R)-10 (30 mg, 0.06 mmol) was submitted to the same conditions as described
20
for (2RS,3S,6R)-10 to afford after purification (3R,6R)-11 (15 mg, 73% yield). [α]D −10.0 (c 0.50,
CH2Cl2); IR 3300, 2977, 2949, 1705, 1538, 1499, 1367, 1346, 1216, 1072, 1035, 914, 835, 789, 770
1
cm−1; H NMR δ 1.18 (br s, 6H), 1.25 (br s, 3H), 1.60–2.20 (m, 4H), 4.70 (dd, J=10.5 and 3.5, 1H),
4.95–5.08 (m, 2H, ABX), 5.95 (1H, ABX), 6.90 (br s, 1H, NH), 7.45–7.95 (m, 7H); HRMS m/z: 339.1837
(calcd for C21H25NO3: 339.1834).
4.15. (3S,6R)-Tetrahydro-6-ethenyl-2,2,6-trimethyl-2H-pyran-3-ol 2
To a solution of (3S,6R)-11 (39 mg, 0.11 mmol) in dry MeOH was added 10% MeONa in MeOH (33
mg, 0.61 mmol of MeONa). The mixture was heated at reflux for 2–3 h under an argon atmosphere,
then cooled to room temperature, diluted with water and extracted with Et2O. The combined organic
layers were treated with a saturated solution of NH4Cl, brine, dried over MgSO4 and concentrated.
The residue was purified by column chromatography on silica gel (hexane:CH2Cl2:EtOAc, 60:30:10)
20
to afford compound 2 (10.5 mg, 54%) as a semisolid oil. [α]D +11.0 (c 0.5, CH2Cl2); IR 3434, 2975,
2938, 1640, 1462, 1402, 1366, 1229, 1190, 1140, 1114, 1075, 1018, 980, 958, 914, 830 cm−1; 1H NMR
δ 1.23 (s, 2× 3H), 1.24 (s, 3H), 1.65–2.05 (m, 4H), 3.43 (m, 1H), 4.92–5.08 (2H, ABX), 5.95 (1H, ABX);

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G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
13C NMR δ 146.8 (d), 110.5 (t), 75.2 (s), 73.6 (s), 71.2 (d), 30.9 (q), 27.5 (t), 27.1 (q), 26.4 (q), 24.2
(t); EIMS C10H18O2 m/z: 155 (M−Me+, 5), 137 (3), 112 (4), 94 (61), 79 (17), 68 (100), 59 (71), 43 (36);
HRMS m/z: 170.1311 (calcd for C10H18O2: 170.1307).
4.16. (3R,6R)-Tetrahydro-6-ethenyl-2,2,6-trimethyl-2H-pyran-3-ol 1
Compound (3R,6R)-11 gave compound 1 according to the same procedure described in Section 4.15;
20
yield 58%; mp 94–95°C; [α]D +1.9 (c 0.5, CH2Cl2); IR 3426, 2975, 2945, 1634, 1450, 1407, 1362,
1229, 1185, 1153, 1114, 1085, 1001, 980, 909, 865, 830, 748 cm−1; 1H NMR δ 1.16 (s, 3H), 1.17 (s, 3H),
1.25 (s, 3H), 1.50–1.77 (m, 3H), 2.13 (m, 1H), 3.44 (m, 1H), 4.95–5.05 (2H, ABX), 5.97 (1H, ABX); 13
C
NMR δ 146.2 (d), 110.6 (t), 75.8 (s), 74.8 (d), 73.4 (s), 32.4 (t), 31.5 (q), 29.4 (q), 25.6 (t), 20.7 (q);
EIMS C10H18O2 m/z: 155 (M−Me+, 2), 137 (2), 102 (3), 97 (3), 94 (65), 79 (14), 68 (100), 59 (71), 43
(29); HRMS m/z: 170.1302 (calcd for C10H18O2: 170.1307).
4.17. (3R,6S)-Tetrahydro-6-ethenyl-2,2,6-trimethyl-2H-pyran-3-ol 3 and (3S,6S)-tetrahydro-6-ethenyl-
2,2,6-trimethyl-2H-pyran-3-ol 4
These compounds were synthesized from (S)-(+)-linalool19 according to the same procedures from 5
through 11 described above for the corresponding enantiomers. Spectral and physical data, except the
opposite signs of optical rotation, were identical to those of the corresponding enantiomers.
Column B (see above) was used for the separation of the four stereoisomers 1–4. The temperature of
the column was increased from 60 to 200°C with a gradient of 1°C min−1. The detector (FID) was at
250°, the glass injector (split ratio 1:30) at 230° and the carrier gas was H2, 1.5 cc min−1. The elution
order of the linalool oxides was found to be: 3R,6S-3 (Rt=23.35 min), 3S,6R-2 (Rt=24.63 min), 3S,6S-4
(Rt=25.42 min) and 3R,6R-1 (Rt=25.96 min).
Acknowledgements
We are indebted to Dr. Mariella Mella and Prof. Giorgio Mellerio for NMR and MS measurements,
respectively. Financial support for this work was provided by the Italian CNR and MURST (ex 40%),
and the EU Commission (Contract No ERBFAIRCT961781).
References
1. Winterhalter, P.; Strauss, C. R.; Wilson, B. Phytochemistry 1980, 19, 1137–1139.
2. Flath, R. A.; Forrey, R. R. J. Agric. Food. Chem. 1977, 25, 103–109.
3. Borg-Karlson, A.-K.; Unelius, C. R.; Valterova, I.; Nilsson, L. A. Phytochemistry 1996, 41, 1477–1483.
4. Boivin, T. L. B. Tetrahedron 1987, 43, 3309–3362.
5. Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321–3408.
6. Jung, M. E.; Fahr, B. T.; D’Amico, D. C. J. Org. Chem. 1998, 63, 2982–2987.
7. Broka, C. A.; Lin, Y.-T. J. Org. Chem. 1988, 53, 5876–5885.
8. Matsuki, Y.; Kodama, M.; Ito, S. Tetrahedron Lett. 1979, 42, 4081–4084.
9. Konstantinovic, S.; Bugarcic, Z.; Milosavljevic, S.; Schroth, G.; Mihailovic, M. L. Liebigs Ann. Chem. 1992, 261–268.
10. Urones, J. G.; Diez, D.; Marcos, I. S.; Basabe, P.; Lithgow, A. M.; Moro, R. F.; Garrido, N. M.; Escarcena, R. Tetrahedron
1995, 51, 3691–3704.
11. Urones, J. G.; Diez, D.; Marcos, I. S.; Basabe, P.; Garrido, N. M.; Escarcena, R.; Lithgow, A. M.; Dominguez, M. F.;
Sanchez, J. M. Synlett 1995, 855–856.

G. Vidari et al. / Tetrahedron: Asymmetry 10 (1999) 3547–3557
3557
12. Scarborough, R. M.; Smith III Jr., A. B.; Barnette, W. E.; Nicolaou, K. C. J. Org. Chem. 1979, 44, 1742–1744.
13. Wrensford, G.; Grab, L. A.; Salvino, J. M.; Williard, P. G. Tetrahedron Lett. 1990, 31, 4257–4260.
14. Felix, D.; Melera, A.; Seibl, J.; Kovats, E. sz. Helv. Chim. Acta 1963, 46, 1513–1536.
15. Corma, A.; Iglesias, M.; Sanchez, F. J. Chem. Soc. Chem. Commun. 1995, 1635–1636.
16. Vidari, G.; Giori, A.; Dapiaggi, A.; Lanfranchi, G. Tetrahedron Lett. 1993, 34, 6925–6928.
17. Méou, A.; Bouanah, N.; Archelas, A.; Zhang, X. M.; Guglielmetti, R.; Furstoss, R. Synthesis 1991, 681–682.
18. Fournier-Nguerfack, C.; Lhoste, P.; Sinou, D. Tetrahedron 1997, 53, 4353–4362.
19. Dorta, R. L.; Rodriguez, M. S.; Salazar, J. A.; Suarez, E. Tetrahedron Lett. 1997, 38, 4675–4678.
20. Nicolaou, K. C.; Claremon, D. A:; Barnette, W. E.; Seitz, S. P. J. Am. Chem. Soc. 1979, 101, 3704–3706.
21. Nicolaou, K. C. Tetrahedron 1981, 37, 4097–4109.
22. Clive, D. I. J.; Chittattu, G. J.; Farina, K.; Kiel, W. A.; Menchen, S. M.; Russell, C. G.; Singh, A.; Wong, C. K.; Curtis, N.
J. J. Am. Chem. Soc. 1980, 102, 4438–4447.