5-Methyl-4H-1,3-dioxins, new chiral building blocks: Transformation into (R)- and (S)-4-hydroxymethyl-4-methyl-1,3-dioxolanes via oxidation and rearrangement and determination of the absolute configuration

Article abstract of DOI:10.1016/j.tetasy.2005.08.046

5-Methyl-4H-1,3-dioxins obtained by asymmetric double-bond isomerization have been transformed into 4-hydroxymethyl-4-methyl-1,3-dioxolanes by m-chloroperbenzoic acid oxidation, ring contraction and reduction. The stereochemical course of this transformat

Full text of DOI:10.1016/j.tetasy.2005.08.046

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3394–3399
5-Methyl-4H-1,3-dioxins, new chiral building blocks:
transformation into (R)- and (S)-4-hydroxymethyl-4-methyl-
1,3-dioxolanes via oxidation and rearrangement and determination
of the absolute configuration
Susanne Flock, Herbert Frauenrath* and Carsten Wattenbach
Fachbereich 18—Naturwissenschaften, Fachgebiet Organische Chemie, Universita¨t Kassel, Heinrich-Plett-Str. 40,
34109 Kassel, Germany
Received 22 August 2005; accepted 30 August 2005
Available online 18 October 2005
Abstract—5-Methyl-4H-1,3-dioxins obtained by asymmetric double-bond isomerization have been transformed into 4-hydroxy-
methyl-4-methyl-1,3-dioxolanes by m-chloroperbenzoic acid oxidation, ring contraction and reduction. The stereochemical course
of this transformation has been studied, while the relative configuration of the intermediate oxidation product and the absolute
configuration of the resulting camphanyl ester of 2-tert-butyl-4-hydroxymethyl-4-methyl-1,3-dioxolane was established by X-ray
crystallography. From these results, the absolute configuration of the dioxins has been deduced.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
demonstrate a practical route for the synthesis of both
enantiomers of compounds 2 and 3 on a multigram
scale.
Previously, we have reported that optically active 5-
methyl-4H-1,3-dioxins 1 can be obtained with high
enantiomeric excess and in high yields by nickel-cata-
lyzed asymmetric double-bond isomerization of 5-meth-
ylene-1,3-dioxanes 4.1 We have also reported that the
one-pot m-CPBA oxidation/acid catalyzed rearrange-
ment of dioxins 1 leads directly to 4-methyl-1,3-dioxo-
lane-4-carbaldehydes 2.1,2
O
O
O
O
O
O
O
O
O
O
R
R
H
H
R
H
H
R
(S)-1
(R)-1
(4S)-2
(4R)-2
OH HO
O
O
Carbaldehydes 2 bearing a quarternary stereogenic
centre in the 4-position and related compounds, for
example, 4-hydroxymethyl-4-methyl-1,3-dioxolanes 3,
have been used as chiral building blocks in a variety of
natural product and asymmetric syntheses.2,3 Therefore,
we have studied the stereochemical course of the latter
transformation in order to establish the hitherto
unknown absolute configuration of dioxins 1 and to
O
R1
O
R
R
R1
(4R)-3
(4S)-3
2. Results and discussion
As a typical example, 2-tert-butyl-5-methylene-1,3-diox-
ane 4a was used as the starting material. Compound 4a
was readily prepared from commercially available 5-
methylene-1,3-propanediol and trimethylacetaldehyde
by acid-catalyzed acetalization.4 The isomerization of
4a was performed with NiBr2[(ꢀ)-Diop] as a precatalyst.
The precatalyst was activated with lithium triethylboro-
hydride at room temperature in ether and then reacted
*
Corresponding author. Tel.: +49 561 8044615; fax: +49 561
8044649; e-mail: frauenrath@uni-kassel.de
Present address: Department of Chemical–Technical Analysis and
Chemical Food Technology, Technical University of Munich,
Weihenstephaner Steig 23, D-85350 Freising-Weihenstephan,
Germany.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.046

S. Flock et al. / Tetrahedron: Asymmetry 16 (2005) 3394–3399
3395
OH
+
OH
O
O
O
O
i
O
i
O
O
H
H
H
O
O
O
O
H
H
+
(2R*,4R*)-( )-3a
(2S*,4R*)-(–)-3a
(2RS,4S*)-2a
4a
(S*)-( )-1a
–
ii
O
O
O
OH
O
O
R'
O
O
ii
iii
O
O
O
O
O
O
O
+
(S*)-( )-1a
–
O
O
O
O
O
H
H
H
H
(2R,4S)-6
(2S,4S)-6
(2S*,4S*,5S*)-( )-5
R' = m-Cl-C6H4
–
(2RS,4S*)-2a
Scheme 2. Reagents and conditions: (i) LiAlH4, Et2O, reflux, 2 h, 95%;
(ii) (1S)-camphanic chloride, pyridine, THF, rt, 3h, 86%.
Scheme 1. Reagents and conditions: (i) 5 mol % NiBr2[(ꢀ)-Diop],
LiBHEt3 (6 mol %, 1.0 M solution in THF), Et2O, rt ! ꢀ70 ꢁC,
addition of 4a, 144 h, 85%, 92% ee; (ii) 1.2 equiv m-CPBA, THF, rt,
4 h, 84%; (iii) Lewatitꢂ MonoPlus S 100 (H+ form), CHCl3, reflux, 1 h,
75%.
capillary column, each of the diastereomers was
obtained as a 96:4 mixture of enantiomers (92% ee).9
This indicates that ring contraction and the following
reduction proceeds without the loss of enantiomeric
purity.
with 4a at ꢀ70 ꢁC to give (ꢀ)-1a with 92% ee in 85%
yield (Scheme 1).2
Coupling of (2S*,4R*)-(ꢀ)-3a with (1S)-camphanic
chloride afforded ester (2S,4S)-6 as a crystalline white
solid, whose absolute configuration was characterized
by X-ray crystallography (Fig. 2).10
Oxidation of (ꢀ)-1a with purified m-chloroperbenzoic
acid5,6 in THF led to a 95:2.3:2.3:0.4 mixture of diaste-
reomers 5 in a virtually quantitative yield. After recrys-
tallization from light petroleum, the main diastereomer
could be isolated from the mixture in a diastereomeri-
cally pure form in 84% yield. The relative configuration
was determined by NMR spectroscopy and unambigu-
ously established by X-ray crystallography as (2S*,
4S*,5S*)-configuration (Fig. 1).7
In the same way, treatment of a 1:1-mixture of
(2RS,4R*)-3a with (1S)-camphanic chloride led to a
mixture of camphanyl esters 6. Interestingly, it was
shown by X-ray crystallography that both diastereomers
crystallize in a single cell, and the absolute configuration
was determined as (2R,4S)- and (2S,4S)-configurations
(Fig. 3).11
Ring contraction was achieved by refluxing (2S*,
4S*,5S*)-5 in either diethyl ether or chloroform in the
presence of a cationic exchange resin, which afforded a
1:1 and 3:1 mixture, respectively, of carbaldehydes
(2S*,4S*)-2a and (2R*,4S*)-2a (Scheme 1). Subsequent
reduction of the mixtures gave the corresponding alco-
hols (2S*,4R*)-3a and (2R*,4R*)-3a (Scheme 2). For
the determination of the enantiomeric purity, diastereo-
mers (2S*,4R*)-3a and (2R*,4R*)-3a were isolated by
column chromatography. By separating on a b-cyclodex
Furthermore, the diastereomeric mixture of alcohols 3a
was transformed into the corresponding benzyl ethers 7
and then into diol (S)-(+)-8 by acetal ring cleavage.
Comparison of the specific rotation with the literature
confirmed the absolute configuration (Scheme 3).3,12
At least, the (R)-enantiomer of diol 8 was prepared by
the same reaction sequence as described above but
Figure 1. ORTEP8 representation of (2S*,4S*,5S*)-(ꢀ)-5 with atomic
labelling scheme showing 40% ellipsoids. H atoms are drawn as small
spheres of arbitrary radii.
Figure 2. ORTEP8 representation of (2S,4S)-6 with atomic labelling
scheme showing 40% ellipsoids. H atoms are drawn as small spheres of
arbitrary radii.

3396
S. Flock et al. / Tetrahedron: Asymmetry 16 (2005) 3394–3399
uration. Hence, together with the known relative config-
uration of 5a, the absolute configuration of (ꢀ)-1a can
be established as an (S)-configuration. This result was
confirmed by transformation of alcohol 3a into benzyl
ether (S)-(+)-8 and comparison of the specific rotation
with the literature values.3,12 The reaction sequence used
for the determination of the absolute configuration of 5-
methyl-4H-1,3-dioxins also demonstrates that these
compounds are useful chiral building blocks for a mul-
tigram scale synthesis of homochiral compounds such
as (S)- and (R)-benzyloxy-2-methylpropane-1,2-diol.
4. Experimental
4.1. General
Figure 3. ORTEP8 representation of (2R,4S)-6 in a mixed crystal of
diastereomers (2RS,4S)-6 with atomic labelling scheme showing 40%
ellipsoids. H atoms are drawn as small spheres of arbitrary radii. The
second splitting position (50% probability) representating diastereomer
(2S,4S)-6 is indicated with dashed bonds and C atoms are drawn as
spheres of arbitrary radii. H atom positions of the disordered group
are not refined.
Solvents were purified according to standard proce-
dures. Analytical TLC was performed using silica gel
60 F254 plates. Column chromatography was performed
using silica gel 60 (0.063–0.200 mm). m-CPBA was pur-
chased from Acros. Melting points are uncorrected and
were measured in open glassware. H and 13C NMR
1
spectra were recorded on a Varian Unity INOVA 500
spectrometer. Chemical shifts are reported in ppm and
coupling constants in Hz. Optical rotations were mea-
sured on a Perkin–Elmer 241 polarimeter in 1 or
10 cm cells. Microanalyses were carried out on a Vario
El analyzer and were in good agreement with the calcu-
lated values. IR spectra were recorded on a Bio-Rad
FTS 40a spectrometer. GC analysis of the enantiomeric
excess of 1a and 3a: GC 8000 Top Serie (CE Instru-
ments), column 30 m · 0.32 mm ID, Rt-bDEXcstTM
(Restek GmbH).9
OBn
O
i
ii
HO
OBn
(2RS,4R)-3a
O
H
HO
(2RS,4R)-7
(S)-(+)-8
Scheme 3. Reagents and conditions: (i) NaH, THF, 0 ꢁC ! rt, BnBr,
Bu4NI, 24 h, 85%; (ii) HCl (10%), THF, 50 ꢁC, 12 h, 85%.
4.2. 2-tert-Butyl-5-methyl-4H-1,3-dioxin (S)-1a
ii - vi
i
HO
OBn
O
O
O
O
HO
NiBr2[(ꢀ)-Diop] (1.15 g, 1.6 mmol) was dissolved in abs.
Et2O at room temperature and activated with LiBHEt3
(1.92 mmol, 1.92 mL, 1 M in THF). After cooling to
ꢀ70 ꢁC, a solution of 4a (5 g, 32 mmol) in abs. Et2O
(25 mL) was added and the mixture left at this tempera-
ture in a deep freezer for 144 h. The conversion of 4a
was monitored by GC. After complete conversion, the
mixture was allowed to warm up to room temperature
and quenched with saturated NH4Cl solution (50 mL).
The organic layer was separated and the aqueous layer
extracted three times with ether. The combined organic
layers were dried (MgSO4). After removal of the solvent,
the residue was distilled in vacuo to give (S)-(ꢀ)-1a as a
H
H
4a
(R)-(+)-1a
(R)-( )-8
–
Scheme 4. Reagents and conditions: (i) 5 mol % NiBr2[(+)-Diop],
LiBHEt3 (6 mol %, 1.0 M solution in THF), Et2O, rt ! ꢀ70 ꢁC,
addition of 4a, 144 h, 85%, 91% ee; (ii) 1.2 equiv m-CPBA, THF, rt,
4 h, 82%; (iii) Lewatitꢂ MonoPlus S 100 (H+-form), CHCl3, reflux, 1 h,
76%; (iv) LiAlH4, Et2O, reflux, 2 h, 96%; (v) NaH, THF, 0 ꢁC ! rt,
BnBr, Bu4NI, 24 h, 85%; (vi) HCl (10%), THF, 50 ꢁC, 12 h, 85%.
starting from (+)-1a. Dioxin (+)-1a was obtained by the
asymmetric double bond isomerization of 4a using
NiBr2[(+)-Diop] as a precatalyst (Scheme 4).
colourless liquid (4.25 g, 27.2 mmol, 85%). Bp 56 ꢁC/12
20
Torr. ½aŠ ¼ ꢀ91:1 (neat); 92% ee (GC). 1H NMR
D
(CDCl3): d 0.95 (s, 9H, C(CH3)3); 1.51 (q, 3H, J = 1.3,
CH@C–CH3); 4.03(ddq, 1H, J = 2.0, J = 1.0, O–
CH2); 4.24 (dqui, 1H, J = 15.1, J = 1.3, O–CH2); 4.33
(s, 1H, O–CHR–O); 6.34 (sext, 1H, J = 1.3, CH@C–
CH3). 13C NMR (CDCl3): d 13.8 (1C, CH@C–CH3);
24.4 (3C, C(CH3)3); 34.3 (1C, C(CH3)3); 68.13(1C, O–
CH2); 103.9 (1C, O–CHR–O); 109.5 (1C, C@CH);
138.5 (1C, C@CH). IR (film): m = 940 cmꢀ1, 955, 990,
1070, 1095, 1115, 1125, 1155, 1215, 1240, 1285, 1365,
1380, 1405, 1440, 1460, 1485, 1650, 1685, 1725, 2670,
2700, 2745, 2845, 2880, 2940, 2960, 2985, 3075. Anal.
3. Conclusions
The absolute configuration of alcohol (2S,4R)-(ꢀ)-3a
derived from 5-methyl-4H-1,3-dioxin (ꢀ)-1a and m-
chlorobenzoic ester 5a was confirmed by X-ray crystal-
lography of the corresponding camphanyl ester. Since
the quaternary stereogenic centre in the 5-position of
ester 5a and in the 4-position of aldehyde 2a, respectively,
is not affected during the rearrangement and reduction,
m-chlorobenzoic ester 5a must have a (2S,4S,5S)-config-

S. Flock et al. / Tetrahedron: Asymmetry 16 (2005) 3394–3399
3397
Calcd for C9H16O2: C, 69.19; H, 10.32. Found: C, 69.15;
H, 10.30.
CHO). 13C NMR (CDCl3): d 18.4 (1C, CH3); 24.3
(3C, C(CH3)3); 34.0 (1C, C(CH3)3); 72.8 (1C, O–CH2);
83.4 (1C, C–CHO); 111.0 (1C, O–CHR–O); 201.8 (1C,
CHO). (2R,4S)-2a 1H NMR (CDCl3): d 0.95 (s, 9H,
C(CH3)3); 1.37 (s, 3H, CH3); 3.65 (d, 1H, J = 8.4, O–
CH2); 4.05 (d, 1H, J = 8.4, O–CH2); 4.69 (s, 1H, O–
CHR–O); 9.70 (s, 1H, CHO). 13C NMR (CDCl3): d
19.1 (1C, CH3); 24.2 (3C, C(CH3)3); 34.4 (1C,
C(CH3)3); 70.7 (1C, O–CH2); 84.1 (1C, C–CHO);
111.1 (1C, O–CHR–O); 202.0 (1C, CHO).
The enantiomer (R)-1a was obtained by the same proce-
dure from 4a (5 g, 32 mmol) and NiBr2[(+)-Diop]
(1.15 g, 1.6 mmol) as
a colourless liquid (4.25 g,
20
27.2 mmol, 85%). ½aŠ ¼ þ90:1 (neat); 91% ee (GC).
D
4.3. 2-tert-Butyl-5-hydroxy-5-methyl-1,3-dioxan-4-yl
3-chlorobenzoate (2S,4S,5S)-5
Acid free m-CPBA (14.88 g, 60.4 mmol) dissolved in
THF (180 mL) was added dropwise at room tempera-
ture to a solution of (ꢀ)-1a (7.86 g, 50.3mmol) in
THF (50 mL). After stirring for 4 h, the mixture was
evaporated in vacuo to dryness. Recrystallization of
the residue from light petroleum (40–60 ꢁC) afforded
The enantiomers (2RS/4R)-2a were obtained from
(2R,4R,5R)-5 (7.33 g, 22.3 mmol) as a colourless liquid
(2.93g, 17.0 mmol, 76%). Anal. Calcd for C 9H16O3: C,
62.77; H, 9.36. Found: C, 62.84; H, 9.48.
4.5. 2-tert-Butyl-4-hydroxymethyl-4-methyl-1,3-dioxo-
lane (2RS,4R)-3a
the pure diastereomer (2S,4S,5S)-5 as a colourless solid
20
(13.91 g, 42.3 mmol, 84%). Mp 98 ꢁC. ½aŠ ¼ ꢀ110:1 (c
D
5, CHCl3). 1H NMR (CDCl3):
d
0.90 (s, 9H,
Aldehydes (2RS,4S)-2a (5.46 g, 31.73 mmol) dissolved
in dry Et2O (30 mL) were added dropwise at room tem-
perature to a suspension of LiAlH4 (0.328 g, 8.63 mmol)
in dry Et2O (50 mL). After complete addition, the reac-
tion mixture was heated to reflux for 2 h. After cooling
to 0 ꢁC, the excess LiAlH4 was destroyed by adding
water. The solid was removed by filtration and washed
with Et2O. The combined organic layers were dried over
MgSO4. Removal of the solvent afforded the diastereo-
mers 3a as a colourless oil (5.25 g, 30.14 mmol, 95%),
which was used in the next step (transformation into
benzylethers 7) without further purification. For the
preparation of camphanoates 6, the diastereomers were
separated by column chromatography (silica, light
petroleum/EtOAc, 85:15). (2S,4R)-3a 1H NMR
(CDCl3): d 0.94 (s, 9H, C(CH3)3); 1.29 (s, 3H, CH3);
2.30 (br s, 1H, OH); 3.46 (d, 1H, J = 11.3, CH2OH);
3.56 (d, 1H, J = 8.1, O–CH2); 3.58 (d, 1H, J = 11.3,
CH2–OH); 3.97 (d, 1H, J = 8.1, O–CH2); 4.62 (s, 1H,
O–CHR–O). 13C NMR (CDCl3): d 20.7 (1C, CH3);
24.3(C3, C( CH3)3); 34.2 (1C, C(CH3)3); 67.5 (1C,
C(CH3)3); 1.53(d, H3 ,
OH); 3.73 (dd, 1H, J = 10.8, J = 1.6, O–CH2eq); 3.95
(dq, 1H, J = 10.8, J = 0.8, O–CH2ax); 4.95 (s, 1H,
J = 0.8, CH3); 2.56 (s, 1H,
O–CHR–O); 6.13(d, 1H,
J = 1.6, O–CH–O–CO);
7.39 (ddd, 1H, J = 7.7, J = 8.0, J = 0.4, Ph–H, C5);
7.55 (ddd, 1H, J = 8.0, J = 1.1, J = 2.2, Ph–H, C4);
7.94 (ddd, 1H, J = 7.7, J = 1.7, J = 1.1, Ph–H, C6);
7.99 (ddd, 1H, J = 1.6, J = 2.1, J = 0.4, Ph–H, C2).
13C NMR (CDCl3): d 23.1 (3C, C(CH3)3); 24.3(1C,
C(CH3)3); 34.2 (1C, CH3); 65.5 (1C, O–CH2); 71.1
(1C, C(CH3)(OH)); 96.4 (1C, O–CH–O–CO); 100.9
(1C, O–CHR–O); 127.8 (1C, Ph, C6); 129.6 (1C, Ph,
C5); 129.8 (1C, Ph, C2); 131.2 (1C, Ph, C1); 133.4 (1C,
Ph, C4); 134.6 (1C, Ph, C3); 164.2 (1C, COOR). IR
(ATR): m = 581 cmꢀ1, 672, 744, 810, 882, 918, 1074,
1105, 1163, 1186, 1259, 1281, 1345, 1429, 1485, 1577,
1692, 1728, 2874, 2964, 3401, 3464. Anal. Calcd for
C16H21ClO5: C, 58.45; H, 6.44. Found: C, 58.51; H
6.44. X-ray data: CCDC 153216.
The enantiomer (2R,4R,5R)-5 was obtained by the same
procedure from (+)-1a (4.25 g, 27.2 mmol) as a pure dia-
stereomer after recrystallization from light petroleum
(40–60 ꢁC). Colourless solid (7.33 g, 22.3 mmol, 82%).
CH2OH); 72.4 (1C, O–CH2); 80.6 (1C, C–CH2OH);
20
109.2 (1C, O–CHR–O). ½aŠ ¼ ꢀ9:3 0 c( 5, CHCl3); 92%
D
ee (GC). Anal. Calcd for C9H18O3: C, 62.04; H, 10.41.
Found: C, 61.94; H, 10.53. (2R,4R)-3a 1H NMR
(CDCl3): d 0.93(s, 9H, C(CH ) ); 1.26 (s, 3H, CH3);
3 3
4.4. 2-tert-Butyl-4-methyl-1,3-dioxolane-4-carbaldehyde
(2RS,4S)-2a
2.30 (br s, 1H, OH); 3.57 (m, 1H, CH2OH); 3.57
(m, 1H, CH2–OH); 3.68 (d, 1H, J = 8.0, O–CH2); 3.86
(d, 1H, J = 8.0, O–CH2); 4.65 (s, 1H, O–CHR–O). 13C
NMR (CDCl3): d 22.0 (1C, CH3); 24.2 (3C, C(CH3)3);
33.9 (1C, C(CH3)3); 66.2 (1C, CH2OH); 72.2 (1C,
(2S,4S,5S)-5 (13.91 g, 42.3 mmol) dissolved in CHCl3 or
Et2O (250 mL) was heated under reflux for 1 h in the
presence of catalytic amounts of a strong acid cation
resin (Lewatitꢂ MonoPlus 100, H+ form). After cooling
to room temperature, the ion exchange resin was removed
by filtration and the reaction mixture washed three times
with saturated NaHCO3 solution and dried over
MgSO4. After filtration and evaporation of the solvent,
the residue was distilled in vacuo to afford the aldehydes
as a colourless liquid. (2RS,4S)-2a (5.46 g, 31.7 mmol,
75%). Bp 56 ꢁC/11 Torr; (2S,4S)-2a/(2R,4S)-2a: 75:25
(from CHCl3); 52:48 (from Et2O). (2S,4S)-2a 1H
NMR (CDCl3): d 0.96 (s, 9H, C(CH3)3); 1.34 (s, 3H,
CH3); 3.59 (d, 1H, J = 9.0, O–CH2); 4.30 (d, 1H,
J = 9.0, O–CH2); 4.74 (s, 1H, O–CHR–O); 9.62 (s, 1H,
O–CH2); 80.4 (1C, C–CH2OH); 111.1 (1C, O–CHR–O).
20
½aŠ ¼ þ7:9 (c 5, CHCl3); 92% ee (GC).
D
The enantiomers (2RS,4S)-3a were obtained by the
same procedure from (2RS,4R)-2a (2.93g, 17 mmol) as
a colourless liquid (2.84 g, 16.3mmol, 96%).
4.6. 2-tert-Butyl-4-methyl-1,3-dioxolane-4-ylmethyl
camphanoate (2S,4S)-6
(1S)-(ꢀ)-Camphanic chloride (1.24 g, 5.47 mmol) was
added slowly to a solution of alcohol (2S,4R)-3a
(1.0 g, 5.74 mmol) and pyridine (0.486 mL, 6.27 mmol)

3398
S. Flock et al. / Tetrahedron: Asymmetry 16 (2005) 3394–3399
in THF (17 mL). After stirring for 3h, Et 2O (20 mL)
was added. The resulting solid was filtered off and
washed with small amounts of Et2O. Concentration of
the combined filtrates afforded the ester as colourless
which was purified by column chromatography (silica,
light petroleum/EtOAc, 95:5; dr 3:1, 6.39 g, 25.62 mmol,
85%). Main diastereomer (2S,4R)-7 H NMR (CDCl3):
1
d 0.92 (s, 9H, C(CH3)3); 1.36 (s, 3H, CH3); 3.53 (d,
1H, J = 8.3, CHR–O–CH2); 3.35 (d, 1H, J = 9.0,
CH2); 3.39 (d, 1H, J = 9.0, CH2); 3.98 (d, 1H, J = 8.3,
CHR–O–CH2); 4.57 (m, 2H, O–CH2–Ph); 4.63(s, 1H,
O–CHR–O); 7.34 (m, 5H, Ph–H). 13C NMR (CDCl3):
d 21.3(1C, CH 3); 24.4 (3C, C(CH3)3); 33.8 (1C,
C(CH3)3); 73.4 (1C, CH2); 73.6 (1C, CH2); 74.9 (1C,
CH2); 79.5 (1C, O–C–CH3); 109.6 (1C, O–CHR–O);
127.5 (2C, Ph); 127.6 (1C, Ph); 128.3(2C, Ph); 138.3
(1C, Ph). Minor diastereomer (2R,4R)-7 1H NMR
1
crystals (1.84 g, 5.1 mmol, 89%). Mp 100 ꢁC. H NMR
(CDCl3): d 0.91 (s, 9H, C(CH3)3); 0.97 (s, 3H, CH3);
1.08 (s, 3H, CH3); 1.12 (s, 3H, CH3); 1.36 (s, 3H,
CH3); 1.70 (ddd, 1H, J = 13.4, J = 9.4, J = 4.3, CH2);
1.94 (ddd, 1H, J = 13.4, J = 10.7, J = 4.6, CH2); 2.05
(ddd, 1H, J = 13.4, J = 9.4, J = 4.6, CH2); 2.44 (ddd,
1H, J = 13.4, J = 10.7, J = 4.3, CH2); 3.56 (dd, 1H,
J = 8.7, J = 0.9, O–CH2ax); 3.93 (d, 1H, J = 9.7, O–
CH2eq); 4.05 (d, 1H, J = 10.9, CH2–O–CO); 4.16 (dd,
1H, J = 10.9, J = 0.9, CH2–O–CO); 4.62 (s, 1H, O–
CHR–O). 13C NMR (CDCl3): d 9.7 (1C, CH3); 16.7
(2C, CH3); 21.1 (1C, CH3); 24.3(3C, C( CH3)3); 28.9
(1C, CH2); 30.6 (1C, CH2); 33.7 (1C, C(CH3)3); 54.2
(1C, C(CH3)2); 54.7 (1C, C–CH3); 68.9 (1C, CH2–O–
CO); 73.2 (1C, O–CH2); 78.0 (1C, C–CH2–O–CO);
91.0 (1C, O(CO)–C–O); 110.0 (1C, O–CHR–O); 167.1
(1C, C–O–CO); 178.0 (1C, CH2–O–CO). IR (film):
m = 443cm ꢀ1, 479, 511, 584, 641, 667, 738, 793, 843,
898, 933, 971, 993, 1019, 1044, 1067, 1106, 1167, 1224,
1272, 1312, 1378, 1402, 1461, 1559, 1650, 1748, 1792,
2361, 2730, 2877, 2972, 3480, 3565, 3651, 3676, 3748.
Anal. Calcd for C19H30O6: C, 64.38; H, 8.53. Found:
C, 64.45; H, 8.49. X-ray data: CCDC 153217.
(CDCl3): d 0.93(s, 9H, C(CH ) ); 1.31 (s, 3H, CH3);
3 3
3.45 (m, 2H, CH2); 3.65 (d, 1H, J = 8.0, CHR–O–
CH2); 3.88 (d, 1H, J = 8.0, CHR–O–CH2); 4.58 (m,
2H, O–CH2–Ph); 4.67 (s, 1H, O–CHR–O); 7.34 (m,
5H, Ph–H). 13C NMR (CDCl3): d 22.5 (1C, CH3); 24.3
(3C, C(CH3)3); 34.1 (1C, C(CH3)3); 72.3(1C, CH 2);
73.4 (1C, CH2); 74.0 (1C, CH2); 79.9 (1C, O–C–CH3);
110.6 (1C, O–CHR–O); 127.5 (2C, Ph); 127.6 (1C, Ph);
128.4 (2C, Ph); 138.2 (1C, Ph). Anal. Calcd for
C16H24O3: C, 72.69; H, 9.15. Found: C, 72.48; H, 9.23.
The enantiomers (2RS,4S)-7 were obtained by the same
procedure from alcohols (2RS,4S)-3a (dr 3:1, 2.84 g,
16.3 mmol) as an oil (dr 3:1, 3.66 g, 13.85 mmol, 85%).
A 1:1 mixture of camphanyl esters 6 (1.75 g, 4.94 mmol,
86%) was obtained from a 1:1 mixture of the corre-
sponding alcohols 3a.
4.8. 3-Benzyloxy-2-methylpropane-1,2-diol (S)-8
HCl (10% aqueous solution, 25 mL) was added to a
solution of (2RS,4R)-7 (6.39 g, 25.62 mmol) in THF
(100 mL) and the reaction mixture was heated to 50 ꢁC
for 12 h. After cooling to room temperature, the mixture
was concentrated in vacuo and extracted three times
with EtOAc (30 mL). The combined organic layers were
dried (MgSO4), concentrated and purified by column
chromatography (light petroleum/Et2O, 3:1) to afford
1
(2R,4S)-6 H NMR (CDCl3): d 0.90 (s, 9H, C(CH3)3);
0.97 (s, 3H, CH3); 1.08 (s, 3H, CH3); 1.13(s, H3 ,
CH3); 1.34 (s, 3H, CH3); 1.70 (ddd, 1H, J = 13.3,
J = 9.3, J = 4.2, CH2); 1.94 (ddd, 1H, J = 13.3,
J = 10.6, J = 4.5, CH2); 2.06 (ddd, 1H, J = 13.3, J =
9.3, J = 4.5, CH2); 2.44 (ddd, 1H, J = 13.3, J = 10.6,
J = 4.2, CH2); 3.67 (d, 1H, J = 8.2, O–CH2); 3.82 (d,
1H, J = 8.2, O–CH2); 4.12 (d, 1H, J = 11.3, CH2–O–
CO); 4.34 (d, 1H, J = 11.3, CH2–O–CO); 4.67 (s, 1H,
O–CHR–O). 13C NMR (CDCl3): d 9.7 (1C, CH3); 16.7
(2C, CH3); 22.2 (1C, CH3); 24.1 (3C, C(CH3)3); 28.9
(1C, CH2); 30.6 (1C, CH2); 34.2 (1C, C(CH3)3); 54.3
(1C, C(CH3)2); 54.8 (1C, C–CH3); 67.6 (1C, CH2–O–
CO); 72.6 (1C, O–CH2); 78.6 (1C, C–CH2–O–CO);
91.1 (1C, O–CO–C–O); 110.8 (1C, O–CHR–O); 167.2
(1C, C–O–CO); 178.1 (1C, CH2–O–CO). X-ray data:
CCDC 153218.
(S)-8 as a colourless oil (4.27 g. 21.78 mmol, 85%),
25
which solidifies on standing. ½aŠ ¼ þ7:0 (c 1.1,
D
CH2Cl2).
The enantiomer (R)-8 was obtained from benzyl ether
(2RS,4S)-7 (3.66 g, 13.85 mmol) by the same procedure
25
D
as a colourless oil (2.31 g, 11.77 mmol, 85%). ½aŠ
¼
ꢀ6:92 (c 1.1, CH2Cl2).
All spectral data were in good agreement with the
literature.3,12
4.7. 4-Benzyloxymethyl-2-tert-butyl-4-methyl-
1,3-dioxolane (2RS,4R)-7
References
1. Frauenrath, H.; Reim, S.; Wiesner, A. Tetrahedron:
Asymmetry 1998, 9, 1103–1106.
2. Wattenbach, C.; Maurer, M.; Frauenrath, H. Synlett
1999, 303–306, and references cited therein.
3. Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.;
Zurbano, M. M. Tetrahedron: Asymmetry 2001, 12, 1383–
1388, and references cited therein.
4. Frauenrath, H. In O/O-Acetale; Hagemann, H., Klamann,
D., Eds.; Houben-Weyl: Methoden der organischen Che-
mie; Georg Thieme: Stuttgart, New York, 1991; E14a/1,
pp 656–657.
Under an inert atmosphere, alcohols 3a (dr 3:1, 5.25 g,
30.14 mmol) were dissolved in dry THF (100 mL) and
the resulting solution added to NaH (0.796 g,
33.15 mmol) at 0 ꢁC. The reaction mixture was allowed
to warm up to room temperature and BnBr (6.24 g,
36.47 mmol) and Bu4NI (3.31 g, 8.95 mmol) added.
After stirring for a further 18 h, the reaction was
quenched by the addition of water (50 mL). Extracting
with EtOAc (100 mL), drying over MgSO4 and removal
of the solvent under reduced pressure afforded crude 7,

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¨
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¨
¨
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