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

Article abstract of DOI:10.1016/S0957-4166(00)00014-8

Each of the four enantiomerically pure tetrahydropyran linalool oxides was synthesized by an acid-catalyzed cyclization of an appropriate epoxy-alcohol obtained by consecutive Sharpless dihydroxylation (AD) and epoxidation (AE) reactions of geraniol derivatives. An interesting example of double asymmetric induction was observed during the AE of a bis(homoallylic) N-naphthylcarbamate. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00014-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 981–989
Enantioselective synthesis of each stereoisomer of the pyranoid
linalool oxides: the geraniol route
Giovanni Vidari,∗ Anna Di Rosa, Francesca Castronovo and Giuseppe Zanoni
Dipartimento di Chimica Organica, Università di Pavia, Via Taramelli 10, 27100 Pavia, Italy
Received 10 December 1999; accepted 6 January 2000
Abstract
Each of the four enantiomerically pure tetrahydropyran linalool oxides was synthesized by an acid-catalyzed
cyclization of an appropriate epoxy-alcohol obtained by consecutive Sharpless dihydroxylation (AD) and epoxida-
tion (AE) reactions of geraniol derivatives. An interesting example of double asymmetric induction was observed
during the AE of a bis(homoallylic) N-naphthylcarbamate. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The four linalool oxides 1 (3R,6R), 2 (3S,6R), 3 (3R,6S), and 4 (3S,6S), as different mixtures of
stereoisomers, have been found as constituents of many flower and fruit aromas, such as grapes and
Carica papaya fruits.1,2 Even as minor constituents of these fragrances, compounds 1–4 are considered
to be important contributors to a particular ‘note’ or ‘character’ of the scent.3
In addition, they probably have a strong biological significance in certain pollination systems, acting
as insect attractants.3 Interestingly, the 2,2,6,6-tetrasubstituted pyran ring is also encountered in a few
marine natural products4–6 as well as in terrestrial fungal metabolites.7 As a part of our ongoing
project on the synthesis of these synthetically appealing natural products,8 we became interested in the
stereoselective synthesis of linalool oxides 1–4, as model compounds for testing general approaches9,10
to enantiomerically enriched substituted pyran ring derivatives. It must be stressed that most previous
syntheses of linalool oxide-like pyran derivatives11–24 were usually poorly stereoselective, giving mix-
∗
Corresponding author. Tel: 0039 0382507322; fax: 0039 0382507323; e-mail: vidari@chifis.unipv.it
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00014-8
tetasy 3237

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tures of cis- and trans-stereoisomers in almost equal amounts. In addition, the latter compounds were of-
ten accompanied by the corresponding isomeric tetrahydrofuran oxides. Recently, we described a highly
enantioselective synthesis of each of the four pyrans 1–4 based on a stereospecific selenocyclization of
the appropriate chiral ∆5-alkenols derived from (R)-(−)- or (S)-(+)-linalool.25 In this paper, we describe
a different strategy centred on a stereospecific acid-catalyzed cyclization of a chiral epoxy-alcohol to
afford the hydroxylated THP ring. Moreover, in contrast to the former chiron-like approach in which the
C-3 stereogenic centre of the starting linalool was preserved through the synthetic pathway, eventually
becoming the C-6 carbon of the final compound, in this variant both stereogenic carbons of the target
compound are introduced into an achiral precursor by two consecutive asymmetric steps.
2. Results and discussion
Based on the general retrosynthetic analysis shown in Scheme 1, each stereoisomer of pyranoid
linalool oxides 1–4 may become available via the stereospecific 6-exo-tet hydroxy epoxide opening of
the corresponding intermediate 5.
Scheme 1. Retrosynthetic analysis
For the sake of simplicity, our approach to compounds 5 was based on the so called ‘naked’
carbon skeleton strategy,26 i.e., selective placement of stereochemically defined oxygen functions onto a
naked unsaturated carbon skeleton. For this goal we planned to use the Sharpless catalytic asymmetric
dihydroxylation (AD)27 and asymmetric epoxidation (AE)28 reactions, which allow the sterecontrolled
functionalization of prostereogenic olefins in a highly predictable way, depending on the chiral ligand
used. Thus, we envisioned the stereodivergent synthesis of each pyranoid linalool oxide in two major
steps using the same starting compound, i.e., the ‘naked’ carbon skeleton of geranyl acetate 6 that already
contains all the carbon atoms of the target products. First, the AD reaction was used to dihydroxylate the
remote double bond of 6, and then the AE reaction was used to epoxidize the allylic double bond.
In principle, the stereochemical issues associated with the synthesis of the four stereoisomers 5 was
thus reduced to a correct combination of the asymmetric inductions of one of the two AD with one of
the two AE reactions. In addition, previous studies29 established that, in order to prevent the undesired
formation of a five-membered THF ring via the highly preferred 5-exo-tet ring closure, construction of
diol 5 required installation of the epoxy ring after the dihydroxylation step and protection of the secondary
hydroxy group. A total of two AD reactions followed by four AE reactions was thus necessary to reduce
our synthetic plan to practice. The synthesis of linalool oxide 1 (Scheme 2) simplifies our synthetic
pathway while in the Experimental, for the sake of clarity, we report only one set of reactions carried out
in the diastereomeric series starting from (6R)-7.
Dihydroxylation of compound 6 with AD-mix-α gave the corresponding triol monoacetate (6S)-7,
91% ee, in 84% yield, while AD-mix-β afforded (6R)-7, 94% ee, in 85% yield after flash chromatography.
In both reactions, dihydroxylation of the 1,2-double bond of compound 6 was <5%, confirming our
previous results.30 Protection of the secondary OH group of stereoisomers 7 was troublesome. Eventually,
it was protected as 1-naphthylcarbamate29 which, compared with other more traditional protective
groups, was smoothly introduced at the severely hindered neopentylic position and proved to be inert

G. Vidari et al. / Tetrahedron: Asymmetry 11 (2000) 981–989
983
Scheme 2. (a) AD-mix-β; (b) (1-naphthyl)NCO; (c) K2CO3, MeOH; (d) L-(+)-DET, Ti(O-i-Pr)4, t-BuOOH; (e) cat. 10-camphor-
sulfonic acid; (f) 1,10-thiocarbonyldiimidazole; (g) P(OMe)3, reflux; (h) 10% MeONa, MeOH, reflux
in the following synthetic steps. Finally, selective hydrolysis of the allylic acetate group provided the key
substrates (6R)- and (6S)-9 which were submitted to the stereodivergent epoxidation steps. Overall yields
of 9 from 7 were in the range of 75–83%. The catalytic variant of the Katsuki–Sharpless AE reaction31 of
(6R)-9, in the presence of L-(+)-diethyl tartrate, afforded (2S,3S,6R)-epoxide 5 as the major stereoisomer,
whereas, in the presence of the D-(−) auxiliary, (2R,3R,6R)-5 was the major one. As expected, starting
from the (6S)-9 enantiomer, L-(+)-diethyl tartrate gave (2S,3S,6S)-5, while D-(−)-tartrate provided the
remaining (2R,3R,6S)-epoxide.
The absolute configuration of these four stereoisomers was proved by that of the final products 1–4.
Epoxides 5 were always accompanied by variable amounts of the corresponding pyran derivatives
10 resulting from an intramolecular etherification reaction which was probably catalyzed by Ti(IV)
species.32 Also, the chromatographic separation of compounds 5 on silica gel gave rise to significant
quantities of cyclic products 10. A sample of (2S,3S,6R)-5, 91% de, was, however, eventually produced
and converted (Scheme 2) into (3R,6R,10S)-10, 90% de, thus demonstrating that the conversion 5→10
occurred with complete stereospecificity. Therefore, we continued our synthesis using crude epoxides
5 which were separately converted into the corresponding pyran derivatives, and the diastereomeric
excess of each starting epoxide was estimated to match that established for the corresponding compound
10. In a series of experiments, overall yields of diastereomerically enriched compounds 10 from 9
were in the range of 26–58%; de of (3R,6R,10S)- and (3S,6S,10R)-10 reached 90–92%, while that of
(3R,6S,10R)- and (3S,6R,10S)-10 was a surprising low 20–25%. These data clearly indicated that the
overall diastereoselectivity observed in the Sharpless AE of allylic alcohols 9 was controlled not only by
the known intrinsic enantiofacial selectivity of the chiral Ti(IV) reagents towards allylic alcohols,28 but
also by the stereodirecting effects of the bis(homoallylic) N-naphthylcarbamoyloxy and tris(homoallylic)
hydroxy groups. Indeed, allylic and homoallylic carbamate groups have been employed to control peroxy
acid epoxidation of olefins and a steering effect similar to that of the corresponding free hydroxy
groups has been found.33 Though we could not find other examples in the literature, we assume that
carbamate groups can also control the stereochemistry of the titanium tartrate ester-catalyzed asymmetric
epoxidation of distant double bonds in a manner similar to that observed for bis(homoallylic) and
tris(homoallylic) alcohols.34 In conclusion, in the epoxidation of olefins 9 we were faced with a relative
new example of substrate–reagent double asymmetric induction in which the combinations (6R)-9+L-
DET and (6S)-9+D-DET constituted the matched pair, while (6R)-9+D-DET and (6S)-9+L-DET formed

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G. Vidari et al. / Tetrahedron: Asymmetry 11 (2000) 981–989
the mismatched pair;35 in the latter reactions, asymmetric induction of the chiral reagent prevailed over
that of the substrate.
Chromatographic separations afforded diastereomerically enriched pyrans 10 which were separately
converted into the corresponding linalool oxides 1–4 by conventional reactions. The four compounds
were eventually produced in high ee and de. In conclusion, the ‘naked’ carbon skeleton strategy26 proved
to be suitable for the divergent asymmetric synthesis of each linalool oxide stereoisomer from abundantly
available achiral geraniol. In addition, though still preliminary, our results show that carbamates may be
useful as neighbouring directing groups to control Sharpless asymmetric epoxidation of prochiral olefins.
3. Experimental
3.1. 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 br=broad are used throughout.
Coupling constants (J) are reported 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. Diastereomeric excesses and enantiomeric excesses were determined by 1H NMR in the
presence of Eu(tfc)3 and/or 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-butyldimethylsilyl-β-CD on
PSO86 capillary column (25 m×0.25 mm id and 0.15 µm film thicknerss) (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 solution containing them.
3.2. Acetic acid (R)-6,7-dihydroxy-3,7-dimethyl-oct-2-enyl ester (6R)-7
AD-mix-β (28.764 g) was added to a stirred 1:1 mixture of t-BuOH:H2O (205 mL), and stirring was
continued at room temperature (25°C) until two bright yellow phases were obtained. MeSO2NH2 (1.940
g, 20.4 mmol) was added, followed by geranyl acetate 6 (4.000 g, 20.4 mmol) at 0°C. The heterogeneous
mixture was stirred vigorously at 0°C for 48 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 dried over MgSO4 and concentrated. The residue was purified by
column chromatography on silica gel (hexane:AcOEt 7:3) to afford (6R)-7, as a colourless oil (4.000 g,
85%, ee 94%). [α]20 +25.2 (c 0.95, CHCl3); IR 3445, 2979, 1725, 1668, 1440, 1380, 1365, 1325, 1240,
D

G. Vidari et al. / Tetrahedron: Asymmetry 11 (2000) 981–989
985
1160, 1080, 1020, 960 cm−1; 1H NMR δ 1.20 (s, 3H), 1.24 (s, 3H), 1.40–1.70 (m, 2H), 1.72 (br s, 3H),
2.10 (s, 3H), 2.10–2.40 (m, 2H), 3.35 (br d, J=10, 1H), 4.65 (d, J=7, 2H), 5.42 (br t, J=7, 1H); 13C NMR
δ 171.1 (s), 141.9 (s), 118.4 (d), 77.1 (d), 72.9 (s), 61.2 (t), 36.4 (t), 29.3 (t), 26.2 (q), 22.9 (q), 20.8 (q),
16.2 (q). Anal. calcd for C12H22O4: C, 62.58; H, 9.63. Found: C, 62.47; H, 9.71.
3.3. Acetic acid (S)-6,7-dihydroxy-3,7-dimethyl-oct-2-enyl ester (6S)-7
Under the same conditions as described for (6R)-7, geranyl acetate 6 (712 mg, 3.63 mmol) was
20
D
dihydroxylated in the presence of AD-mix-α to afford (6S)-7 (699 mg, 84%, ee 91%). [α] −24.2
(c 1.1, CHCl3). The IR, 1H NMR and 13C NMR data were identical to those of the enantiomer (6R)-7.
3.4. Acetic acid (R)-7-hydroxy-3,7-dimethyl-6-(naphthalen-1-ylcarbamoyloxy)-oct-2-enyl ester (6R)-8
Dry pyridine (12 mL, 0.148 mmol), followed by N-1-naphthylisocianate (3.526 g, 20.84 mmol), was
added to a solution of (6R)-7 (4.0 g, 17.36 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 complete hydrolysis of excess N-1-naphthylisocyanate.
The mixture was then filtered through a pad of Celite. 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
20
silica gel (hexane:AcOEt 3:2) to afford (6R)-8 (6.3 g, 91%). [α] +9.8 (c 1.0, CH2Cl2); IR 3330–3420
D
1
(OH and NH), 2975, 2936, 1718, 1540, 1499, 1373, 1231, 1105, 1048, 1025, 792, 771, 665 cm−1; H
NMR δ 1.26 (br s, 6H), 1.70 (s, 3H), 1.70–1.92 (m, 2H), 2.05 (s, 3H), 2.05–2.30 (m, 2H), 4.59 (d, J=7,
2H), 4.79 (dd, J=10 and 2, 1H), 5.38 (br t, J=7, 1H), 7.18 (br s, 1H, NH), 7.40–8.00 (7H, ArH); 13C NMR
δ 170.86 (s), 154.89 (s), 141.04 (s), 133.99 (s), 132.41 (s), 128.51 (d), 127.07 (s), 126.07 (d), 125.84 (d),
125.62 (d), 125.21 (d), 120.59 (d), 119.80 (d), 118.79 (d), 80.79 (d), 72.42 (s), 51.12 (t), 35.78 (t), 27.81
(t), 26.46 (q), 24.98 (q), 20.75 (q), 16.32 (q); EIMS C23H29NO5 m/z 399 (M+, 22), 187 (99), 170 (24),
169 (97), 152 (21), 143 (100), 115 (27), 109 (36), 94 (22), 81 (53), 71 (35), 69 (24), 59 (27), 57 (22), 55
(22), 43 (77), 41 (20).
3.5. Naphthalen-1-yl-carbamic acid (R)-6-hydroxy-1-(1-hydroxy-1-methyl-ethyl)-4-methyl-hex-4-enyl
ester (6R)-9
Powdered K2CO3 (2.074 g, 15 mmol), followed by H2O (0.5 mL), was added to a solution of acetate
(6R)-8 (5.900g, 14.78 mmol) in MeOH (150 mL). The mixture was stirred at rt for 3 h and then quenched
by addition of 5% HCl and extracted with AcOEt. The solvent was evaporated and the residue purified
by column chromatography on silica gel (hexane:AcOEt 65:35 to 50:50) to afford (6R)-9 (4.780 g, 91%).
20
D
[α] +5.0 (c 2.3, CH2Cl2); IR 3330, 3053, 2976, 2933, 1704, 1540, 1501, 1379, 1258, 1228, 1105,
1004, 793, 771 cm−1; 1H NMR δ 1.20 (br s, 6H), 1.62 (s, 3H), 1.60–1.90 (m, 2H), 2.00–2.20 (m, 2H),
2.35 (br s, 1H, OH), 2.79 (br s, 1H, OH), 4.10 (m, 2H), 4.80 (dd, J=10 and 2, 1H), 5.43 (br t, J=7, 1H),
7.33–7.95 (8H, NH and ArH). EIMS C21H27NO4 m/z 357 (M+, 26), 188 (24), 187 (77), 170 (38), 169
(80), 152 (15), 143 (78), 127 (14), 115 (45), 109 (36), 94 (15), 81 (63), 71 (31), 69 (25), 59 (32), 55 (22),
43 (100), 41 (27). Anal. calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C, 70.65; H, 7.54; N,
3.88.

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G. Vidari et al. / Tetrahedron: Asymmetry 11 (2000) 981–989
3.6. Naphthalen-1-yl-carbamic acid (R)-2-hydroxy-1-[2-((2S,3S)-3-hydroxymethyl-2-methyl-oxiranyl)-
ethyl]-2-methyl-propyl ester (2S,3S,6R)-5
A mixture of powdered, commercially activated 4 Å molecular sieves (100 mg) and dry CH2Cl2 (3 mL)
was cooled to 0°C. L-(+)-DET (14.1 mg, 68.38 mmol) and Ti(O-i-Pr)4 (13.9 mg, 48.9 mmol) were added
sequentially. After the mixture was cooled to −20°C, t-butyl hydroperoxide (0. 360 mL, 1.96 mmol, 5.5
M in nonane) was added and the resulting mixture was stirred for 20 min, whereupon (6R)-9 (350 mg,
0.98 mmol, in 0.5 mL of dry CH2Cl2) was slowly added dropwise. Vigorous stirring was maintained at ca.
−20°C for 20 h. After the reaction mixture was warmed to 0°C, H2O was added (ca. 20 times the weight
of Ti(O-i-Pr)4 used in the reaction) and the mixture was stirred for 40 min, while allowing it to warm to
room temperature. Hydrolysis of tartrates was then effected by adding 1 mL of a 30% aqueous solution
of NaOH saturated with NaCl. After 15 min of vigorous stirring, a sudden phase separation occurred.
The lower organic phase was removed and combined with two CH2Cl2 extracts of the aqueous phase. In
some experiments where work-up was difficult, TBHP was reduced by using a solution of FeSO4·7H2O.
Drying over MgSO4, followed by filtration through a pad of Celite and evaporation of volatiles, provided
a white solid (340 mg, 93%) which was used in the following step. An analytical sample of (2S,3S,6R)-
20
D
5, mp 156–157°C, [α] −5.0 (c 0.8, MeOH), was obtained by column chromatography on silica gel
(from hexane:AcOEt 25:75 to 100% AcOEt). IR 3460, 2981, 1738, 1704, 1537, 1503, 1464, 1373, 1240,
1045, 848, 783 cm−1; 1H NMR (CD3OD) δ 1.15–1.40 (3 br s, 9H), 1.55–1.95 (m, 4H), 2.96 (br t, 1H,
ABX), 3.60 (dd, 1H, ABX), 3.75 (dd, 1H, ABX), 4.75 (br d, J=10, 1H), 7.38–8.05 (m, 7H, ArH); 13C
NMR (CD3OD) δ 158.1 (s), 135.9 (s), 134.9 (s), 130.2 (s), 129.6 (d), 127.4 (d), 127.3 (d), 127.2 (d),
126.8 (d), 123.5 (d), 123.2 (d), 81.9 (d), 73.3 (s), 64.7 (d), 62.3 (s), 61.9 (t), 36.7 (t), 26.8 (q), 26.4
(t), 17.2 (2 q). EIMS C21H27NO5 m/z 373 (M+, 7), 312 (12), 187 (30), 169 (70), 143 (98), 125 (27),
116 (17), 115 (37), 109 (11), 97 (11), 81 (14), 71 (38), 69 (16), 59 (18), 57 (14), 55 (19), 43 (100), 41
(21). Diastereomeric excess was estimated to be ca. 91% by integration of the 13C NMR signals of the
corresponding diastereoisomers.
3.7. Naphthalen-1-yl-carbamic acid (R)-2-hydroxy-1-[2-((2R,3R)-3-hydroxymethyl-2-methyl-oxiranyl)-
ethyl]-2-methyl-propyl ester (2R,3R,6R)-5
(6R)-9 (1.500 g, 4.201 mmol) was submitted to D-(−)-DET (78 mg, 0.38 mmol) and Ti(O-i-Pr)4 (83.6
mg, 0.29 mmol) under the same conditions as indicated in Section 3.6 to afford crude (2R,3R,6R)-5
(1.097 g, 70%) which was used immediately in the following step.
3.8. Naphthalen-1-yl-carbamic acid (3R,6R)-6-[(S)-1,2-dihydroxy-ethyl]-2,2,6-trimethyl-tetrahydro-
pyran-3-yl ester (3R,6R,10S)-10
A solution of crude epoxide (2S,3S,6R)-5 (180 mg, 0.48 mmol) in CH2Cl2 was cooled to 0°C. A
catalytic amount of (1S)-10-camphorsulfonic acid was added and the reaction mixture was stirred at the
same temperature for a period of 2 h. The solution was neutralized by adding 5% aq. NaHCO3, dried
over MgSO4 and then evaporated. Separation by column chromatography on silica gel (CH2Cl2:AcOEt
1:1) afforded 126 mg of pyran derivatives 10 (71% yield) and 6 mg of rearranged product 13.

G. Vidari et al. / Tetrahedron: Asymmetry 11 (2000) 981–989
987
Integration of the two signals at δ 4.65 (minor diastereomer) and 4.80 (major diastereomer) in the
1H NMR spectrum of 10 showed a diastereomeric excess of 91%. Separation of the two diastereomeric
products by flash column chromatography on silica gel (hexane:AcOEt 25:75) afforded 110 mg of the
20
major diastereomer (3R,6R,10S)-10. [α] −19.3 (c 1.5, CH2Cl2); IR 3408, 3053, 2978, 2934, 1702,
D
1542, 1500, 1382, 1235, 1217, 1107, 1068, 1018, 792, 771, 736, 701 cm−1; 1H NMR (at 50°C) δ 1.17 (s,
3H), 1.24 (s, 3H), 1.30 (s, 3H), 1.80–2.20 (m, 4H), 2.65 (br s, 1H, OH), 2.89 (br s, 1H, OH), 3.35 (br, 1
H), 3.62 (br, 2H), 4.80 (br s,1H), 7.15 (br s, 1H, NH), 7.38–7.97 (7H, ArH); 13C NMR δ 154.1 (s), 134.1
(s), 132.3 (s), 128.6 (d), 126.3 (d), 126.0 (d), 125.6 (d), 125.4 (d), 120.7 (s), 78.0 (s), 76.2 (d), 74.0 (s),
72.5 (d), 62.4 (t), 27.4 (q), 27.3 (q), 23.3 (q), 23.2 (t), 20.6 (t); EIMS C21H27NO5 m/z 373 (M+, 14), 312
(59), 188 (17), 170 (18), 169 (69), 143 (59), 125 (66), 115 (16), 109 (16), 97 (17), 81 (18), 71 (40), 69
(21), 57 (23), 55 (22), 43 (100), 41 (20). Anal. calcd for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found:
C, 67.63; H, 7.38; N, 3.64.
3.9. Naphthalen-1-yl-carbamic acid (3R,6S)-6-[(R)-1,2-dihydroxy-ethyl]-2,2,6-trimethyl-tetrahydro-
pyran-3-yl ester (3R,6S,10R)-10
Crude (2R,3R,6R)-5 (1.057 g, 2.83 mmol) was submitted to the same conditions as indicated in Section
3.8 to afford pyran derivatives 10 (693 mg, 66% yield) as a mixture of diastereoisomers. Integration of
1
the two signals at δ 4.60 (major diastereoisomer) and 4.77 (minor diastereoisomer) in the H NMR
spectrum showed a diastereomeric excess of 20%. Separation of this mixture by column chromatography
on silica gel (hexane:AcOEt 25:75) afforded 388 mg of the major diastereoisomer and 257 mg of the
20
minor one. (3R,6S,10R)-10), white crystalline solid; mp 175–176°C; [α] −6.7 (c 1.0, CH2Cl2); H
1
D
NMR δ 1.10–1.30 (br s, 9 H), 1.80–2.20 (m, 4 H), 2.66 (br s, 1H, OH), 2.89 (br s, 1H, OH), 3.40 (m,
1H), 3.58 (m, 2H), 4.65 (br s, 1H), 6.98 (br s, 1H, NH), 7.38–7.97 (7H, ArH); 13C NMR δ 153.7 (s),
134.0 (s), 132.2 (s), 128.7 (d), 126.2 (d), 125.9 (d), 125.6 (d), 125.4 (d), 120.4 (s), 77.8 (d), 76.9 (d), 76.1
(s), 74.2 (s), 62.4 (t), 30.7 (q), 29.8 (q), 29.7 (t), 22.1 (q), 21.4 (t). Anal. calcd for C21H27NO5: C, 67.54;
H, 7.29; N, 3.75. Found: C, 67.44; H, 7.36; N, 3.68.
3.10. Naphthalen-1-yl-carbamic acid (3R,6R)-2,2,6-trimethyl-6-vinyl-tetrahydro-pyran-3-yl ester (3R,
6R)-12
A mixture of the diol (3R,6R,10S)-10 (104 mg, 0.278 mmol) and N,N0-thiocarbonyldiimidazole (TCDI,
50 mg, 0.278 mmol) in dry toluene (4 mL) was heated at reflux for 1.5 h under an argon atmosphere.
The solvent was then removed by evaporation (azeotrope with MeOH). Purification of the crude product
by column chromatography on silica gel (hexane:AcOEt 1:1) gave thiocarbonate (3R,6R,10S)-11 (71 mg,
61%); IR 3300, 3050, 2981, 2948, 1714, 1598, 1537, 1498, 1384, 1293, 1214, 1177, 1104, 1071, 978,
1
793, 735 cm−1. H NMR δ 1.10–1.45 (3 br s, 9H), 1.70–2.15 (m, 4H), 4.58–4.78 (m, 4H), 6.90 (br
s, 1H NH), 7.40–7.97 (7H). EIMS C22H25NO5S m/z 415 (M+, 27), 187 (32), 169 (36), 143 (49), 125
(19), 115 (18), 109 (17), 81 (17), 71 (40), 69 (16), 57 (16), 55 (17), 43 (100), 41 (17). A solution of
the thiocarbonate 11 (70 mg, 0.168 mmol) and freshly distilled P(OMe)3 (2 mL) was heated at reflux
for 24 h under an argon atmosphere.36 Excess of P(OMe)3 was removed by distillation under reduced
pressure. Separation of the residue by column chromatography on silica gel (hexane:AcOEt 4:1) afforded
16 mg of unreacted thiocarbonate 11 and (3R,6R)-12 (42.2 mg, 74% yield, 95% on the recovered starting
20
20
1
material); [α] −10.5 (c 1.0, CH2Cl2) [lit.25] [α] −10.0 (c 0.5, CH2Cl2); IR and H NMR spectra
D
D
were identical with the literature.25

988
G. Vidari et al. / Tetrahedron: Asymmetry 11 (2000) 981–989
3.11. Naphthalen-1-yl-carbamic acid (3R,6S)-2,2,6-trimethyl-6-vinyl-tetrahydro-pyran-3-yl ester (3R,
6S)-12
Following the same procedure as described in Section 3.10, diol (3R,6S,10R)-10 (290 mg, 0.77 mmol)
gave thiocarbonate (3R,6S,10R)-11 (203 mg, 63%) which was subsequently converted into (3R,6S)-12
20
1
(114 mg, 69% yield). [α] −16.9 (c 1.3, CH2Cl2); IR and H NMR spectra were identical with the
D
corresponding spectra of the enantiomer (3S,6R)-12 reported in the literature.25
3.12. (3R,6R)-2,2,6-Trimethyl-6-vinyl-tetrahydro-pyran-3-ol 1
To a solution of (3R,6R)-12 (40 mg, 0.12 mmol) in dry MeOH was added 10% MeONa in MeOH
(33 mg, 0.61 mmol of MeONa). The mixture was heated at reflux for 3 h under an argon atmosphere,
then cooled to room temperature, diluted with H2O, 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:AcOEt 60:30:10) to afford
20
D
compound 1 (19 mg, 93%); [α] +2.1 (c 1.0, CH2Cl2); IR 3426, 2975, 2945, 1634, 1450, 1407, 1362,
1229, 1185, 1153, 1114, 1085, 1001, 980, 909, 865, 830 748, 698 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 (m, 2H, ABX), 5.97 (1H,
ABX). The data matched those reported in the literature.19,22,25,37,38
3.13. (3R,6S)-2,2,6-Trimethyl-6-vinyl-tetrahydro-pyran-3-ol 3
Compound (3R,6S)-12 (85 mg, 0.25 mmol) gave compound 3 (30 mg, 71%) according to the same
20
D
procedure described in Section 3.12; [α] −11.5 (c 1.0, 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, 4 H), 3.43 (m, 1H), 4.92–5.08 (2H, ABX), 5.95 (1H, ABX). The data matched
those reported in the literature.19,22,25,37,38
3.14. (3S,6R)-2,2,6-Trimethyl-6-vinyl-tetrahydro-pyran-3-ol 2 and (3S,6S)-2,2,6-Trimethyl-6-vinyl-
tetrahydro-pyran-3-ol 4. Diastereomeric and enantiomeric excesses
The title compounds were synthesized from geranyl acetate 6 according to the procedures from
6 through 12 described above for the corresponding enantiomers, and employing AD-mix-α and L-
(+)-DET, and AD-mix-α and D-(−)-DET, respectively, in the two asymmetric steps. Spectral and
physical data, except the opposite signs of optical rotation, were identical to those of the corresponding
enantiomers reported in previous sections.
The four stereoisomers 1–4 could be separated on an enantioselective GC column (column B, see
above) using the conditions indicated in a previous paper.25 The enantiomeric excess of each stereoisomer
was >98%, while the diastereomeric excesses were: 1, 99%; 2, 90%; 3, 97%; 4, 90%, respectively.
Acknowledgements
We thank Dr. Mariella Mella and Prof. Giorgio Mellerio for NMR and MS measurements, respectively.
Prof. Carlo Bicchi of the University of Turin is acknowledged for enantioselective GC analysis. Financial

G. Vidari et al. / Tetrahedron: Asymmetry 11 (2000) 981–989
989
support for this work was provided by the Italian CNR and MURST (ex. 40%), and the EU Commission
(Contract No. ERBFAIRCT961781).
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