A short and efficient asymmetric synthesis of (-)-frontalin, (-)-exo-isobrevicomin and a volatile contributor of beer-aroma

Article abstract of DOI:10.1016/j.tet.2010.05.032

The natural products, (-)-frontalin and (+)-exo-isobrevicomin were synthesized employing Sharpless asymmetric epoxidation and ZrCl ₄-catalyzed intramolecular acetalization as the key steps. (-)-Frontalin was synthesized in three steps with a 61

Full text of DOI:10.1016/j.tet.2010.05.032

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Tetrahedron 66 (2010) 5701e5706
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A short and efficient asymmetric synthesis of (ꢀ)-frontalin,
(ꢀ)-exo-isobrevicomin and a volatile contributor of beer-aroma
*
Surendra Singh, Patrick J. Guiry
Center for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The natural products, (ꢀ)-frontalin and (þ)-exo-isobrevicomin were synthesized employing Sharpless
asymmetric epoxidation and ZrCl4-catalyzed intramolecular acetalization as the key steps. (ꢀ)-Frontalin
was synthesized in three steps with a 61.4% overall yield and 89.9% ee and (ꢀ)-exo-isobrevicomin also
obtained in an overall satisfactory yield of 10.1% and 97% ee. We have also synthesized the volatile
contributor of beer aroma in a 96% ee.
Received 3 February 2010
Received in revised form
28 April 2010
Accepted 10 May 2010
Available online 13 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
substituted tetrahydropyrans, which were useful synthons for an
asymmetric synthesis of (þ)-exo- and (þ)-endo-brevicomin.6
Natural products with a 6,8-dioxabicyclo[3.2.l]octane skeleton
have attracted much attention because of their intriguing biological
activities; examples include the aggregation pheromones frontalin
1, brevicomin 2, and isobrevicomin 3. (ꢀ)-Frontalin is known to be
the aggregation pheromone of the southern pine beetle, Den-
droctunus frontalis, isolated by Kinzer and co-workers1 and (1S, 5R)-
1,5-dimethyl-6,8-dioxabicyclo[3.2.1] octane is its biologically active
form, whereas its enantiomer has been reported to be inactive.2
(ꢀ)-exo-Isobrevicomin 3, (1S, 5R, 7S)-5-ethyl-7-methyl-6,8-dioxa-
bicyclo[3.2.1]octane, was isolated from the male mountain pine
beetle, Dendroctonus ponderosae in 1996 by Francke and co-workers
and its structure confirmed by synthesis starting from (þ)-tartaric
acid.3
Herein, we wish to disclose a further extension of this synthetic
methodology in a short and efficient synthesis of (ꢀ)-frontalin
and (ꢀ)-exo-isobrevicomin.
Numerous asymmetric syntheses of frontalin 1 have been
reported but the development of a short synthetic route with good
overall yield was lacking and therefore of interest.7 Our retro
synthetic plan for the synthesis of (ꢀ)-1S, 5R-frontalin 1, outlined in
Scheme 1, proposed that the key quaternary carbon stereocentre in
4 was to be synthesized by the ring opening of (þ)-epoxide 5 with
the Grignard reagent derived from 2-(2-bromoethyl)-2-methyl-1,3-
dioxolane (6).
Thus, (þ)-epoxide 5 was synthesized in 87% yield, employing
Sharpless asymmetric epoxidation using 10 mol % of Ti(OiPr)4 and
15 mol % of (ꢀ)-DIPT as the source of chirality and cumene hydro-
peroxide as oxidant at ꢀ20 ꢁC for 36 h (Scheme 2). The ring opening
of epoxide 5 was carried out at ꢀ78 ꢁC in THF using a catalytic
amount of CuI (10 mol %) with 3 equiv of the Grignard reagent
derived from 2-(2-bromoethyl)-2-methyl-1,3-dioxolane (6). The
diol 4 was treated with ZrCl4 (10 mol %) in methanol under mi-
crowave irradiation (150 W) for 10 min to afford (ꢀ)-frontalin in an
86% yield and 89.9% ee. The enantiomeric excess was determined
O
O
O
O
O
O
1: Frontalin
2: exo-Brevicomin
3: exo-Isobrevicomin
During
methodologies of use in total synthesis, we have recently dis-
covered a ZrCl4-catalyzed formation of
-lactones.4 We sub-
sequently exploited this in an asymmetric synthesis of both
enantiomers of mosquito attractant pheromones.5 We have also
reported an extension of our investigations in this area in which
we described a microwave-assisted, asymmetric synthesis of
a study to develop new protection/deprotection
by GC using a chiral b-dex column and its absolute configuration
was determined by comparison with literature optical rotations.8
We were unable to determine the enantioselectivity of the epoxi-
dation step but can infer it from the enantiomeric excess of 1 as our
previous work in this area had not found any loss of stereochem-
istry in the final cyclization step.5 The unnatural enantiomer
(þ)-1R, 5S-frontalin 1 was synthesized in 92.8% ee, using the same
synthetic sequence starting with the enantiomer of epoxide 5.
We were also keen to apply this synthetic sequence to the syn-
thesis of (ꢀ)-exo-isobrevicomin 3, isolated from the male mountain
d
* Corresponding author. E-mail address: patrick.guiry@ucd.ie (P.J. Guiry).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.032

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S. Singh, P.J. Guiry / Tetrahedron 66 (2010) 5701e5706
HO
O
O
O
O
O
OH
+
Br
O
O
OH
1
4
5
6
Scheme 1.
O
HO
(S)
i
BrMg
(–)-DIPT, Ti(OPr)4
O
(S)
O
O
O
OH
THF, 78 °C, CuI,
82% yield
CH2Cl2, –35 °C to –20 °C,
cumene hydroperoxide,
36 h, 87% yield
OH
OH
5
4
10 mol % ZrCl4
°C,
MW (150 W), 10 min
86% yield
O
(S)
(R)
O
1
Scheme 2.
pine beetle, Dendroctonus ponderosae.3 Unlike frontalin, there have
been relatively few reported syntheses of (ꢀ)-exo-iso-
brevicomin.9aee These include a low yielding (23.1%) chiral pool
approach starting from (þ)-tartaric acid,9a and catalytic asymmetric
synthesis approaches using Sharpless asymmetric dihydroxylation
of (E)-2-ethyl-2-(hex-4-enyl)-5,5-dimethyl-1,3-dioxane as the key
step in a synthesis that proceeded in 3.57% overall yield9b and 99% ee
and 5-ethyl-2-furfural followed by oxidative furan ring-expansion
reaction to give 3 in 17% overall yield and 92.5% ee.9c
Our synthesis of (ꢀ)-exo-isobrevicomin commenced with the
synthesis of epoxide 7 (35% yield) employing the Sharpless
asymmetric epoxidation protocol10a at ꢀ20 ꢁC for 36 h (Scheme 3).
(2S, 3R)-1,2-Epoxy-3-butenol (7) was converted into its p-nitro-
benzoate ester 8 in 79% yield using Mitsunobu reaction con-
ditions.10b Hydrolysis of this benzoate ester 8 in methanol using
K2CO3 afforded (2S, 3S)-1,2-epoxy-3-butenol (9) in 76% yield. The
ring opening of epoxide 8 was performed at ꢀ78 ꢁC using a cata-
lytic amount of CuI (10 mol %) and the Grignard reagent derived
from 2-(2-bromoethyl)-2-ethyl-1,3-dioxolane (10) at 50 ꢁC in THF.
2-(2-Bromoethyl)-2-ethyl-1,3-dioxolane (10) was synthesized in
a 70% yield from pent-1-en-3-one, 1.2 equiv of TMSBr and an
excess of ethylene glycol. The intramolecular acetalization of anti-
diol 11 was performed in methanol using a catalytic amount of
ZrCl4 under microwave irradiation to afford (ꢀ)-exo-isobrevicomin
3 in 87% yield and 97.9% ee. The enantiomeric excess11 of (ꢀ)-exo-
isobrevicomin was determined by GC using a chiral b-dex column
and its absolute configuration was confirmed by comparison with
literature optical rotations.8
We have also explored this synthetic sequence for the synthesis
of the (S)-enantiomer of 7,7-dimethyl-6,8-dioxabicyclo[3.2.1]oc-
tane (16) which is known as a volatile contributor to the aroma of
beer12 and was first isolated from Japanese hop oil.13 The asym-
metric synthesis of beer aroma 15 has been accomplished using
tartaric acid as the chiral starting material,14a,b through reso-
lution,14c or via asymmetric cycloaddition employing Oppolzer’s
chiral sultam,14d Sharpless dihydroxylation14e and enantio-
convergent biocatalytic hydrolysis of trisubstituted epoxides.14f
We also wished to investigate a synthetic sequence employing
the ring opening of an enantioenriched epoxide, following by ring
opening and subsequent ZrCl4-catalyzed acetalization for the syn-
thesis of beer aroma 16. The Sharpless asymmetric epoxidation of
2-methylbut-3-en-2-ol in the presence of 10 mol % Ti(OiPr)4 and
O
O
(–)-DIPT, Ti(O-i-Pr)4
p-Nitrobenzoic acid, PPh3
CH2Cl2, –20 °C, cumene
hydroperoxide, 36 h
35% yield
°C
79% yield
OH
rt
OCOC6H4-p-NO2
OH
7
8
K2CO3
MeOH
76% yield
rt
°C
2 h, 70% yield
+ 1,2-ethylene glycol + TMSBr (1.2 equiv.)
O
O
O
Mg,
Br
OH
O
O
O
10 mol % ZrCl4
O
10
HO
°C,
O
THF, –78 °C, CuI,
79% yield
OH
MW (150 W), 10 min
87% yield
3
11
9
Scheme 3.

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S. Singh, P.J. Guiry / Tetrahedron 66 (2010) 5701e5706
5703
15 mol %
L
-(þ)-DIPT and cumene hydroperoxide at ꢀ20 ꢁC afforded
In summary we have developed a short and efficient synthesis
of (ꢀ)-frontalin, the aggregation pheromone of the pine bark beetle
in three steps with 61.4% overall yield and 89.9% ee. We have
synthesized (ꢀ)-exo-isobrevicomin in six steps with 10.1% overall
yield and 97.9% ee. We have also synthesized the volatile beer
aroma in 96% ee. All syntheses had the Sharpless asymmetric
epoxidation/HKR of racemic epoxide and our ZrCl4-catalyzed
bicyclic ring formation as the key steps.
epoxide 13 in 30% yield with poor enantioselectivity (44% ee),
Scheme 4.
i
O
(–)-DIPT, Ti(O Pr)4
CH2Cl2, –20°C, cumene
hydroperoxide, 36 h
30% yield
OH
OH
13; 44% ee
12
Scheme 4.
2. Experimental
Racemic epoxide 13 was synthesized using a standard epoxida-
tion procedure employing m-CPBA. Then we applied the hydrolytic
kinetic resolution (HKR)15 of racemic epoxide 13 in the presence of
1 mol % of (R, R)-Jacobsen Co(III)OAc and we obtained epoxide 13
(96% ee) in 30% isolated yield over 5 days (Table 1, entry 1).
2.1. General remarks
2-Methylprop-2-en-1-ol,
pent-1-en-3-one,
but-3-en-2-ol,
(þ)-and (ꢀ)-diisopropyltartrate, Ti(Oi-Pr)4, 3-butene-2-one, TMSBr,
ZrCl4, anhydrous methanol, 1,2-ethylene glycol, p-nitrobenzoic
Table 1
HKR of epoxide 13 using (R, R)-Jacobsen Co(III) salen
O
OH
OH
N
O
(R,R)-Jacobsen Co(III)X
N
O
O
+
Co
X
H2O, rt
OH
OH
OH
(-)-13
13
A; X = OAc
B; X = PF6
Entrya
Catalyst
Reaction time
Catalyst loading (mol %)
ee of epoxide 13b
Isolated yield of epoxide 13
1
2
3
A
B
B
5 days
15 h
8 h
1
0.5
1
96
79
99.9
30
40
25
a
The Jacobsen Co(III)X (0.5e1 mol %) dissolved in the epoxide 13 and 0.5 equiv of water was added slowly at 0e5 ꢁC and then the reaction mixture was stirred at a room
temperature for the time mentioned.
b
The enantiomeric excess of epoxide 13 was determined by Chiral GC using a b-dex column.
In addition, we altered the cobalt counterion from ꢀOAc to ꢀPF6,
which we found to be more active in the HKR of racemic epoxide 13
leading to reaction completion in 8 h with 99.9% ee (Table 1, entry
3). In contrast, 0.5 mol % catalyst loading afforded epoxide 13 in 40%
isolated yield and in 79% ee after 15 h (Table 1, entry 2). The
enantioenriched (96% ee) epoxide 13 was converted to diol 14 in
a 73% isolated yield using the Grignard reagent derived from
2-bromoethyl-1,3-dioxane in the presence of catalytic amounts of
CuI (Scheme 5). The diol 14 was then treated with ZrCl4 in methanol
under microwave irradiation to give the 6-methoxytetrahy-
dropyran 15 in 85% yield. The cyclization of compound 15 using
FeClO4 (0.2 equiv) in dichloromethane then afforded the volatile
contributor of beer aroma 16 in 75% yield and 96% ee.
acid, DIAD, CuI, and Mg turnings were obtained from commercial
sources and were used as received. Proton and carbon nuclear
magnetic resonance spectra (1H and 13C NMR, respectively) were
recorded on a 400 MHz Varian-Unity FT spectrometers (operating
frequencies: 1H, 400.13 MHz; 13C, 100.61 MHz) at ambient tem-
perature. In the case of 1H and 13C NMR spectra, the chemical shifts
(d) for all compounds are listed in parts per million downfield from
tetramethylsilane using the NMR solvent as an internal reference.
The reference values used for deuterated chloroform (CDCl3) were
7.26 and 77.00 ppm for 1H and 13C NMR spectra, respectively. High
resolution mass spectra were measured on a Waters/Micromass
instrument. Optical rotation values were measured on a Perkin-
Elmer polarimeter. GC analysis was done using a Schimadzu 2010
O
OH
ZrCl4, MeOH,
MW (150W)
60 °C, 3min, 85%
OH
O
O
OMe
OH
BrMg
O
O
HO
O
THF, –35 °C, 73% yield
13; 96% ee
14
15; dr (3:1)
FeClO4.3H2O
CH2Cl2, 75% yield
O
O
16; 96% ee
Scheme 5.

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S. Singh, P.J. Guiry / Tetrahedron 66 (2010) 5701e5706
instrument using a chiral
b
-dex column. Thin layer chromatography
were dissolved in methanol (1.5 mL) and irradiated under MW
(150 W) at 60 ꢁC for 10 min. The compound was purified by flash
column chromatography using pentane/Et2O (9:1) as the eluent but
as 1 was volatile, so the solvent was evaporated by rotavapor at 40 ꢁC
was carried out using Merck Kieselgel 60 F254 silica gel plates.
Column chromatography separations were performed using Merck
Kieselgel 60 (Art. 7734). Solvents were dried immediately before
use by distillation from standard drying agents. Molecular sieves
(4 Å) were activated by heating overnight in an oven at 120 ꢁC.
andthe remainingsolvent wasremoved at 40 ꢁC at 150 mbar vaccum,
20
to give (ꢀ)-frontalin 1 as a colorless oil (287 mg, 86% yield).7t
[a]
D
24
ꢀ53.6 (c 1.44, 89.9% ee, Et2O) [lit.7h
[a]
19 ꢀ53.7 (c 0.67, Et2O), lit.7j
[a
]
D
D
2.2. Experimental procedures and spectroscopic data for all
compounds
ꢀ50.3 (c 1.63, 89.1%ee, Et2O), and lit.7t
[a
]D ꢀ51.6 (c 0.5, 85% ee, Et2O)];
Rf (pentane/Ether, 9:1)¼0.75; dH 1H NMR (400 MHz, CDCl3) 3.90 (1H,
d, J 6.7 Hz, eOCH2e), 3.44 (1H, dd, J 6.7, 1.5 Hz, eOCH2e), 1.94e1.79
(1H, m, eCH2eCH2eCH2), 1.69e1.48 (5H, m, eCH2eCH2eCH2), 1.42
(3H, s, OeCeCH3), 1.31 (3H, s, OeCeCH3); dC 13C NMR (101 MHz,
CDCl3) 108.0, 80.0, 74.2, 34.5, 33.9, 24.7, 23.0, 18.0 ppm; GCeHRMS
(EI), found 142.0994 [M]þ, C8H14O2 requires 142.0994.
2.2.1. Synthesis of epoxide 5. A mixture of crushed 4 Å activated
molecular sieves (1.0 g) and CH2Cl2 (30 mL) was cooled to ꢀ35 ꢁC,
titanium tetraisopropoxide (0.71 mL, 3 mmol) and (R, R)-(ꢀ)-DIPT (0.
96 mL, 4.5 mmol) were added by syringe. After the mixture was
stirred at ꢀ35 ꢁC for 30 min, 2-methyl-prop-2-en-1-ol (2.34 g,
30 mmol) was added by addition funnel, followed by cumene hy-
droperoxide (6.98 mL, 45 mmol). The reaction mixture was stirred at
ꢀ35 ꢁC for 1 h and then stirred at ꢀ20 ꢁC for 35 h. Aqueous saturated
Na2SO4 (3 mL) was added and the mixture was diluted with Et2O
(30 mL). After the mixture wasstirred at ambient temperature for 3 h,
the resulting slurry was filtered through a pad of Celite, and the
resulting yellow solution was concentrated. Excess cumene alcohol
and cumene hydroperoxide were removed by silica gel chromatog-
raphy (pentane/EtOAc, 4:1 then 100% Et2O). Kugelrohr distillation
2.2.3.1. (1R,5S)-1,5-Dimethyl-6,8-dioxa-bicyclo[3.2.1]octane (1).
All physical data are identical to (1S, 5R)-1 apart from [
a
]
[
20 þ52.3 (c
D
a
1.05, 92.8% ee, Et2O) [lit.7e
[
a
]
D
20 þ54.3 (c 0.3, Et2O), lit.7c
]
21 þ52.4
D
(c 4.0, Et2O)].
2.2.4. Synthesis of epoxide 7. A mixture of crushed activated 4 Å
molecular sieves (2.0 g) and CH2Cl2 (80 mL) was cooled to ꢀ35 ꢁC,
and titanium tetraisopropoxide (5.92 mL, 20 mmol) and (R, R)-
(ꢀ)-DIPT (6.30 mL, 30 mmol) were added by syringe. After the
mixture was stirred at ꢀ35 ꢁC for 30 min, but-3-en-2-ol (6.9 mL,
80 mmol) was added by addition funnel, followed by cumene hy-
droperoxide (8.3 mL, 56 mmol). The reaction mixture was stirred at
ꢀ35 ꢁC for 1 h and then stirred at ꢀ20 ꢁC for 35 h. The reaction
work up and purification were performed identical to the synthesis
of epoxide 7.10a Kugelrohr distillation (120 ꢁC, 5 mbar) provided 7 as
(120 ꢁC, 5 mbar) provided 5 as a colorless oil (2.30 g 87%).7d
[a]
20 þ9.1
D
25
(c 2.05, CHCl3) [lit.7d
[a]
þ10.7 (c 2.0, CHCl3)]; Rf (pentane/EtOAc,
D
4:1)¼0.57; dH 1H NMR (400 MHz, CDCl3) 3.71 (1H, dd, J 12.3, 4.6 Hz,
HOeCH2), 3.59 (1H, dd, J 12.3, 8.4 Hz, HOeCH2), 2.90 (1H, d, J 4.8 Hz,
OeCH2), 2.64 (1H, d, J 4.8 Hz, OeCH2),1.99 (1H, dd, J 8.4, 4.6 Hz, eOH),
1.35 (3H, s, Me); dC 13C NMR (101 MHz, CDCl3) 64.2, 57.2, 51.0,
18.0 ppm. GCeHRMS (EI), found 88.0521 [M]þ, C4H18O2 requires
88.0524.
a colorless oil (2.47 g, 35%). [
a
]
20 ꢀ47.5 (c 1.1, CHCl3) [lit.7 [
a
]
26 ꢀ16.9
D
D
(c 1.16, MeOH)]; Rf (pentane/EtOAc, 4:1)¼0.42; dH 1H NMR
(400 MHz, CDCl3) 3.99e3.91 (1H, m,CH3eCHeOH), 2.98 (1H, dt, J
4.0, 3.2 Hz, OeCH2e), 2.79e2.74 (1H, m, OeCH2e), 2.71 (1H, dd, J
5.2, 4.0 Hz, OeCH2e), 2.11 (1H, br s, eOH), 1.23 (3H, d, J 6.4 Hz,
eCHeCH3); dC 13C NMR (101 MHz, CDCl3) 64.7, 55.3, 43.4, 18.6 ppm.
GCeHRMS (EI), found 88.0526 [M]þ, C4H8O2 requires 88.0524.
2.2.2. (S)-2-Methyl-5-(2-methyl-1,3-dioxolan-2-yl)pentane-1,2-diol
(4). The Grignard derivative of 2-methyl-(2-bromoethyl)-1,3-di-
oxane was prepared by slow addition of the bromide (3.14 mL,
15 mmol) to preactivated magnesium turnings (3.60 g, 15 mmol) in
THF (15 mL) with 1,3-dibromoethane as initiator (30 mL, 0.33 mmol)
at 50 ꢁC and then stirred for 45 min. The solution was then trans-
ferred to a two-necked flask containing copper (I) iodide (0.5 mmol)
at ꢀ78 ꢁC and stirred for 5 min. The epoxide (440 mg, 5 mmol) in
THF (5 mL) was added dropwise over 20 min and stirring was con-
tinued for a further 1 h at ꢀ78 ꢁC. Solid ammonium chloride (0.60 g)
was added and the solution was stirred at room temperature for
10 min after which time a saturated ammonium chloride solution
(15 mL) was added. The solution was extracted with ethyl acetate
(6ꢂ40 mL) and the combined organic layers were washed with
water (30 mL), brine (30 mL), and dried over magnesium sulfate.
After removal of the solvent in vacuo the residue was purified by
column chromatography using silica gel (pentane/EtOAc¼4:1/1:1
and then ethyl acetate). The compound 4 isolated as a pale yellow oil
2.2.5. Synthesis of (R)-1-((R)-oxiran-2-yl)allyl 4-nitrobenzoate (8).
PPh3 (752 mg, 4.5 mmol) and p-nitrobenzoic acid (1.180 g, 4.5 mmol)
were dissolved inTHF (6 mL) and DIAD (826 mL, 4.2 mmol) was added
dropwise at 0 ꢁC.10b Then the epoxide 7 (264 mg, 3 mmol) in THF
(2 mL) was added slowly and stirred for 5 min at 0 ꢁC and then
warmed to room temperature. The reaction mixture was stirred for
55 minatroom temperature and the majorityofsolvent wasremoved
under reduced pressure. The residue was purified by column chro-
matography using pentane/EtOAc (9:1) as the eluent. Compound 8
20
(565 mg, 79% yield)wasisolated asalightyellowsolid, mp51 ꢁC;[
a]
D
þ41.0 (c 1.42, CHCl3); Rf (pentane/EtOAc, 9:1)¼0.65; nmax (KBr) 3115,
2997,1729,1273,1103 cmꢀ1 dH 1H NMR (400 MHz, CDCl3) 8.26(4H, td,
J
9.0, 6.8 Hz, OeCO-p-NO2eC6H4e), 5.03 (1H, p, J 6.4 Hz,
20
20
(856 mg, 82%).7t
[
a
]
ꢀ1.8 (c 1.40, CHCl3) [lit.7t[
a
]
ꢀ2.1 (c 1.0,
CH3eCHeCHe), 3.26 (1H, ddd, J 6.4, 4.0, 2.4 Hz, OeCHeCH2e),
3.00e2.85 (1H, m, eOeCH2e), 2.73 (1H, dd, J 4.8, 2.4 Hz, eOeCH2e),
1.49 (3H, d, J 6.4 Hz, eCHeCH3); dC 13C NMR (101 MHz, CDCl3) 163.8,
150.6, 135.5, 130.8, 123.5, 73.0, 53.4, 44.6, 16.5 ppm; GCeHRMS (EI),
found 194.0457 [MꢀC2H4O]þ, C9H8NO4 requires 194.0448.
D
D
Et2O)]; Rf (pentane/EtOAc, 1:1)¼0.48; dH 1H NMR (400 MHz, CDCl3)
4.04e3.84 (4H, m, eOCH2eCH2eO), 3.46 (H, d, J 10.9 Hz, HOeCH2),
3.39 (H, d, J 10.9 Hz, HOeCH2)1.67e1.62 (2H, m, eCeCH2eCH2),
1.56e1.39 (4H, m, CH2eCH2eCH2eC),1.31 (3H, s, anomeric-CH3),1.16
(3H, s, eOHeC(CH2)eCH3); dC (101 MHz, CDCl3) 110.0, 72.8, 69.7,
64.6, 64.5, 39.5, 38.6, 23.7, 23.2, 18.3; HRMS (ESI), found 227.1387
[MþNa]þ, C10H20O4Na requires 227.1259.
2.2.6. Synthesis of (1R, 2R)-1,2-epoxy-ethanol (9). The p-nitro-
benzoate 8 (500 mg, 2.1 mmol) and K2CO3 (700 mg) were added to
methanol (4 mL) at 0 ꢁC and stirred for 5 min.10b The reaction
mixture was sonicated for 1 min and then filtered through a pad of
silica gel and washed with diethyl ether (30 mL). The solvent was
removed under reduced pressure and the residue was purified by
2.2.2.1. (R)-2-Methyl-5-(2-methyl-1,3-dioxolan-2-yl)pentane-1,2-
diol (4). All physical data are identical to (S)-4 apart from [
(c 1.30, CHCl3).
a]
20 þ1.8
D
column chromatography using pentane/Et2O (1:1) to give (1R, 2R)-
20
2.2.3. Synthesis of (1S, 5R)-1,5-dimethyl-6,8-dioxa-bicyclo[3.2.1]oc-
tane (1). ZrCl4 (55 mg, 10 mol %) and diol 4 (480 mg, 2.35 mmol)
1,2-epoxy-ethanol (9) as a liquid (140 mg, 76% yield). [
a
]
D
þ19.3
(c 1.0, CHCl3); Rf (pentane/EtOAc, 4:1)¼0.42; nmax (liquid film) 3420,