Org. Synth. 1998, 75, 170
DOI: 10.15227/orgsyn.075.0170
(1'S,2'S)-METHYL-3O,4O-(1',2'-DIMETHOXYCYCLOHEXANE-1',2'-DIYL)-α-D-MANNOPYRANOSIDE
[
α-D-Mannopyranoside, methyl 3,4-O-(1,2-dimethoxy- 1,2-cyclohexanediyl)-, [3[S(S)]]-
]
Submitted by Steven V. Ley, Helen M. I. Osborn, Henning W. M. Priepke, and Stuart L. Warriner
1
.
Checked by Karl A. Scheidt and William R. Roush.
1. Procedure
A.
1,1,2,2-Tetramethoxycyclohexane
(Note 1). A 500-mL, two-necked flask equipped with a stirrer bead, condenser and heating mantle is flushed with dry argon and then charged with
44.8 g of 1,2-cyclohexanedione (0.400 mol),
100 mL of dry methanol (MeOH) and
160 mL of trimethyl orthoformate (1.46 mol)
(Note 2). Stirring is begun and approximately 32 drops of concd sulfuric acid are added to the solution. The resultant black solution is heated under argon at reflux for 5 hr. The heating mantle is removed and the solution is cooled to room temperature. Sodium hydrogen carbonate is carefully added to neutralize the solution (approx 4 g required). Methanol, methyl formate and trimethyl orthoformate are removed by distillation at ambient temperature through a straight path distillation apparatus. The residue is then distilled under reduced pressure to yield 59.5 g of
1,1,2,2-tetramethoxycyclohexane
as a colorless liquid (73%) (Note 3), (Note 4).
B.
(1'S,2'S)-Methyl-3O,4O-(1',2'-dimethoxycyclohexane-1'2'-diyl)-α-D-mannopyranoside
. A 500-mL, two-necked flask equipped with a stirrer bead, condenser and heating mantle is flushed with dry argon and charged with
30 g of methyl-α-D-mannopyranoside (0.15 mol),
300 mL of dry MeOH,
59.5 g of 1,1,2,2-tetramethoxycyclohexane (0.29 mol) and
16.1 g of trimethyl orthoformate (0.15 mol).
Camphorsulfonic acid (CSA), 3.48 g, (0.015 mol) is added and the resultant black solution is heated under argon at reflux for 16 hr. The heating mantle is removed and the solution is cooled to room temperature.
Sodium bicarbonate is carefully added to neutralize the solution (approx 5 g required)
(Note 5). The mixture is transferred to a 1-L, round-bottomed flask, and the solvent is removed under reduced pressure on a rotary evaporator
(Note 6). The crude material (Note 7) is purified by column chromatography on silica gel (1.5 Kg of silica gel using a 10-15 cm diameter column; gradient elution
0-5%
ethanol in ether
) followed by crystallization from ethyl acetate-hexane
(Note 8) to yield 20.8-23.2 g of
(1'S,2'S)-methyl-3O,4O-(1',2'-dimethoxycyclohexane-1',2'-diyl)-α-D-mannopyranoside
as colorless cubes (41-46%) (Note 9).
2. Notes
1.
All materials are commercially available from Aldrich Chemical Company, Inc., Acros Organics or Avocado Research Chemicals, Ltd. (Shore Road, Port of Heysham Industrial Park, Heysham, Lancashire, LA3 2XY, England). It is recommended that MeOH be distilled from
calcium hydride prior to use.
2.
Trimethyl orthoformate acts as a drying agent in both Step A and B. It is therefore advantageous to use an excess of this drying agent to force the reaction to completion.
3.
Physical data for purified material are as follows: bp
76°C at 0.8 mm Hg.
1H NMR (CDCl
3) δ: 1.31-1.48 (m, 4 H), 1.60-1.75 (m, 4 H), 3.32 (s, 12 H)
;
13C NMR (CDCl
3) δ: 21.67, 30.61, 49.25, 102.07
; IR (neat) cm
−1: 2950, 2880, 2840, 1520, 1500, 1480, 1350, 1340, 1200, 1150, 1100, 1050, 960, 870
; HRMS calcd for C
10H
20O
4 m/z 204.1361, found 204.1363
. Anal. Calcd for C
10H
20O
4: C, 58.80; H, 9.87. Found: C, 58.60; H, 9.68.
4.
The checkers obtained
59.7-64.1 g (
73-78%) of
1,1,2,2-tetramethoxycyclohexane.
5.
This neutralization step should be performed for at least 20 min. During this period, the reaction turns from an indigo to a light brown color.
6.
Concentration of the crude product should be stopped when solids begin to form. The checkers observed that it was difficult to dissolve the crystalline crude product in ether to load the column for chromatographic purification.
7.
The crude product consists mainly of the desired product; protection of the cis-2,3-diol occurs only to a minor extent. The major side product from the reaction is the
1,3-dioxolane, which can be slowly converted to the required product under thermodynamic equilibrating conditions; i.e., further treatment of the
dioxolane with boiling
methanol and a trace of CSA for 4 days produced the required product in 35% yield together with recovery of the
dioxolane in 16% yield.
8.
The chromatographed product is dissolved in
160 mL of boiling ethyl acetate
and then diluted with
150 mL of hexanes. The solution was allowed to cool to room temperature, and then placed in a −20°C freezer overnight. The crystalline product was collected by filtration and washed with cold hexanes.
9.
Physical data for purified material are as follows: mp
173°C (EtOAc-hexane);
[α]
D
25 +170° (CHCl
3,
c 0.95);
1H NMR (CDCl
3) δ: 1.29-1.43 (m, 2 H), 1.45-1.55 (m, 2 H), 1.62-1.82 (m, 4 H), 2.25 (br, t, 1 H, J = 5.8), 2.89 (s, 1 H), 3.20 (s, 3 H), 3.21 (s, 3 H), 3.35 (s, 3 H), 3.72-3.86 (m, 3 H), 3.92 (br, s, 1 H), 4.14 (dd, 1 H, J = 10.6, 2.9), 4.25 (dd, 1 H, J = 2 × 10.0), 4.72 (d, 1 H, J = 0.9)
;
13C NMR (CDCl
3) δ: 21.27 (2 x), 26.88, 26.91, 46.71, 46.82, 54.77, 61.18, 63.64, 68.77, 69.88, 70.73, 98.64, 99.10, 101.59
; IR (KBr) cm
−1: 3500-3400, 3000, 3050, 2820, 1400, 1350, 1340, 1200-1000, 900, 850, 820, 800, 790, 750, 700
; HRMS calcd for C
15H
26O
8, m/z 334.1628, found 334.1639
. Anal. Calcd for C
15H
26O
8: C, 53.88; H, 7.84. Found: C, 53.77; H, 7.73. The submitters reported mp
168°C (ether);
[α]
D
25 +191° (CHCl
3,
c 0.94).
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Until recently, the protection of the trans-hydroxyl groups of sugars has been an inefficient process.
2 This protection has now been simplified by the introduction of the dispiroketal protecting group,
3 and the
cyclohexane diacetal (CDA) protecting group.
4 As shown in this report, the CDA protecting group is easily introduced, and the present procedure allows facile protection of the trans-hydroxyl groups of a range of sugars.
|
|
SUGAR
|
3,4-protected
|
2,3-protected
|
|
|
|
45%
|
11%
|
|
|
53%
|
10%
|
|
|
74%
|
8%
|
|
|
45%
|
11%
|
|
|
30%
|
50%
|
|
The ease of selective protection can be explained in terms of maximum anomeric stabilization such that both anomeric methoxy groups of the product are oriented in the axial position with respect to the central dioxane ring. All four sterically demanding alkyl substituents are then placed in the favored equatorial positions. The poor selectivity for the protection of glucose results from the existence of
two
pairs of trans-hydroxyl groups in this sugar.
The CDA protecting group has been shown to withstand common sugar derivatization reactions,
4 and is easily removed under acidic conditions.
4 Further, it has proved possible to tune the reactivity of sugars via the introduction of the CDA protecting group, and this in turn has allowed concise syntheses of complex oligosaccharides.
5
6
7
8
9
Further research within in our laboratory has illustrated that certain substrates bearing trans-hydroxyl groups can be directly protected using cyclic and acyclic diones, thus alleviating the requirement for prior formation of the tetramethoxydiacetals.
10
11 For example,
butane-2,3-dione has proved particularly useful for the preparation of butane diacetal (BDA) derivatives, which serve as useful alternatives to cyclohexane diacetal (CDA) derivatives.
This preparation is referenced from:
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(1'S,2'S)-Methyl-3O,4O-(1',2'-dimethoxycyclohexane-1',2'-diyl)-α-D-mannopyranoside:
α-D-Mannopyranoside, methyl 3,4-O-(1,2-dimethoxy-1,2-cyclohexanediyl)-, [3[S(S)]]- (13); (163125-35-7)
1,1,2,2-Tetramethoxycyclohexane:
Cyclohexane, 1,1,2,2-tetramethoxy- (13);(163125-34-6)
1,2-Cyclohexanedione (8,9); (765-87-7)
Trimethyl orthoformate:
Orthoformic acid, trimethyl ester (8);
Methane, trimethoxy- (9);
(149-73-5)
Methyl formate:
Formic acid, methyl ester (8,9); (107-31-3)
Camphorsulfonic acid monohydrate (CSA):
Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (±)- (9); (5872-08-2)
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