SHORT PAPER
An Efficient and Highly Stereoselective Synthesis of gala-Quercitol from 1,4-Cyclohexadiene
1501
[1R(S),2S(R),4S(R),5S(R)]-4,5-Dibromocyclohexane-1,2-diol
(7)16
yield (Scheme 1). We especially point out that all steps
proceed with yields over 90%.
A 50 mL three-necked, round-bottomed flask equipped with a mag-
netic stirrer and a nitrogen inlet, was charged with NMO (0.91 g,
7.78 mmol), H2O (10 mL), and acetone (5.0 mL). To this solution
were added OsO4 (ca. 20 mg) and 4,5-dibromocyclohexene (6)
(1.61 g, 6.7 mmol). The resulting mixture was stirred vigorously un-
der nitrogen at r.t. During the overnight stirring, the reaction mix-
ture became homogeneous. After 24 h, the reaction was complete.
Sodium hydrosulfite (1.0 g) and Florisil (5 g) slurried in H2O (2 mL)
were added, the slurry was stirred for 10 min, and the mixture was
filtered through Celite (10 g). The pH of the filtrate was adjusted to
3 using aq HCl (0.5 M). Acetone was removed under reduced pres-
sure (25 mmHg, 30 °C). The organic phase was extracted with
EtOAc (3 × 50 mL) and dried (Na2SO4). Removal of the solvent
gave trans-4,5-dibromocyclohexane-cis-1,2-diol (7).
The formation of 9 as the sole product may be questioned.
A similar elimination reaction was previously observed
by treatment of 1,2-dibromocyclohexane with NaOMe to
give 3-methoxycyclohexene17 as the major product in a
yield of 60%.
The first step in the formation of 9 is the HBr elimination.
As seen from Scheme 2, two bromine atoms at C5 and C6
are suitable for the elimination reaction. However, the top
face of the molecule is sterically hindered for the abstrac-
tion of axial protons H4axial by the syn-methyl group of the
ketal functionality. Therefore, the base attacks exclusive-
ly the proton H7axial to give the allylic bromide 11 with an
anti-configuration of the bromine atom. An SN2 attack of
methoxide at C5 results in the formation of the key com-
pound 9, where the methoxyl and ketal group have the de-
sired configuration for the synthesis of gala-quercitol.
Yield: 1.65 g (90%); mp 103–104 °C (recystallized from CH2Cl2)
(lit. mp 103–105 °C14).
1H NMR (200 MHz, CDCl3): = 4.40–3.80 (m, 4 H), 3.70 (br s, 1
H), 3.13 (br s 1 H), 2.60–1.99 (m, 4 H).
13C NMR (50 MHz, acetone-d6): = 72.3, 72.1, 56.9, 56.1, 44.3,
42.1.
Sterically hindered face
[3aR(S),5S(R),6S(R),7aS(R)]-5,6-Dibromo-2,2-dimethylhexahy-
dro-1,3-benzodioxole (8)16
H3C
H3C
CH3
Br
MeO-
O
O
To a solution of trans-4,5-dibromocyclohexane-cis-1,2-diol (7)
(2.57 g, 9.38 mmol) in CH2Cl2 (50 mL) was added 2,2-dimethoxy-
propane (1.30 g, 12.5 mmol) and TsOH (100 mg). The mixture was
stirred at r.t. for 3 h. The solution was filtered over basic Al2O3 (10
g). Evaporation of the solvent gave ketal 8.
CH3
H
7a
3a
6
7
9
O
O
-MeOH
5
4
H
Br
-OMe
Br
11
8
Yield: 2.85 g (97%); colorless oil.
Scheme 2
1H NMR (200 MHz): = 4.39 (dt, 1 H, J = 7.5, 4.0 Hz), 4.29–4.09
(m, 3 H), 2.70 (dt, 2 H, J = 15.0, 4.0 Hz), 2.32 (ddd, 1 H, J = 15.0,
7.9, 6.2 Hz), 2.18 (ddd, 1 H, J = 14.9, 8.3, 5.0 Hz), 1.49 (s, 3 H),
1.29 (s, 3 H).
13C NMR (50 MHz): = 110.9, 74.6, 74.1, 53.2, 51.0, 38.3, 36.8,
30.2, 28.5.
In summary, with relatively little synthetic effort we have
achieved the stereoselective synthesis of DL-gala-quercit-
ol in seven steps starting from commercially available
1,4-cyclohexadiene (overall yield of 68%) and introduced
the complex stereochemistry in a very simple way. We
suppose that 9 may be used as a versatile precursor for
preparation of different cyclitol derivatives.
(3a ,5 ,7a )-5-Methoxy-2,2-dimethyl-3a,4,5,7a-tetrahydro-
1,3-benzodioxole (9)
To magnetically stirred MeOH (50 mL) was added sodium (0.50 g,
21.7 mmol) and then a solution of 8 (2.00 g, 6.37 mmol) in MeOH
(5 mL) at r.t.. The reaction mixture was stirred at r.t. for 6 h. After
removal of MeOH at reduced pressure the residue was dissolved in
CCl4 and the solution filtered over an Al2O3 (basic, 10 g) column.
Removal of the solvent gave 9.
Mps are uncorrected. IR spectra were obtained from KBr pellets on
a Mattson 1000 FT-IR spectrophotometer. The H and 13C NMR
1
spectra were recorded on a Varian 200 MHz spectrometer. Appar-
ent splittings are given in all cases. Column chromatography was
performed on silica gel (60–200 mesh, Merck). TLC was carried out
on Merck 0.2 mm silica gel 60 F254 analytical aluminum plates.
Yield: 1.13 g (96%); colorless oil.
IR: 3037, 2987, 2933, 2825, 1381, 1316, 1247, 1216, 1170, 1143,
1112, 1062, 1008, 958 cm–1.
4,5-Dibromocyclohexene (6)16,18
1H NMR (200 MHz) = 5.93–5.96 (dm, A part of AB system, 1 H,
J = 11.0 Hz), 5.81 (ddd, B part of AB system, 1 H, J = 11.0, 3.5, 2.0
Hz), 4.35–4.37 (m, 1 H), 4.17 (dt, 1 H, J = 10.9, 5.4 Hz), 3.67–3.71
(m, 1 H), 3.31 (s, 3 H), 2.23–2.14 (m, 1 H), 1.50–1.39 (m, 1 H), 1.38
(s, 3 H), 1.27 (s, 3 H).
13C NMR (200 MHz): = 136.4, 126.3, 111.5, 76.2, 74.3, 72.7,
57.7, 34.2, 30.3, 28.0.
To a stirred solution of 1,4-cyclohexadiene (35.0 g, 0.44 mol) in
hexane (600 mL) was added dropwise a solution of bromine (70.0
g, 0.44 mol) in hexane (200 mL) at –45 °C over 4 h. After bromine
addition was completed, the mixture was warmed to r.t. The precip-
itate was filtered off and discarded. Evaporation of the solvent un-
der reduced pressure gave 4,5-dibromocyclohexene.
Yield: 100.3 g (95% isolated yield); white crystals; mp 34–36 °C
(lit.16 34–37 °C).
1H NMR (200 MHz, CDCl3): = 5.65 (m, 2 H), 4.58 (m, 2 H), 3.17
(dm, A part of AB system, J = 20 Hz), 2.60 (dm, B part of AB sys-
tem, 2 H, J = 20 Hz).
Anal. Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 64.88; H,
8.56.
5-O-Methyl-gala-quercitol Tetraacetate (10)
13C NMR (50 MHz, CDCl3): = 124.0, 50.5, 33.0.
To a solution of NMO (1.39 g, 11.9 mmol) in H2O (5 mL) was add-
ed methoxy ketal 9 (2.00 g, 10.9 mmol). Under N2 atmosphere,
OsO4 (19 mg) was added and the resulting mixture was stirred for
Synthesis 2003, No. 10, 1500–1502 © Thieme Stuttgart · New York