Org. Synth. 2000, 77, 212
DOI: 10.15227/orgsyn.077.0212
METHYL 2,3-O-(6,6'-OCTAHYDRO-6,6'-BI-2H-PYRAN-2,2'-DIYL)-α-D-GALACTOPYRANOSIDE
[
α-D-Galactopyranoside, methyl, 2,3-O-(octahydro[2,2'-bi-2H-pyran]-2,2'-diyl-, [2(2R,2'R)-]
]
Submitted by Steven V. Ley
1
and Helen M.I. Osborn
2
.
Checked by Laurent Ducry, Leïla Abrous, and Amos B. Smith, III.
1. Procedure
Caution! tert-Butylithium is extremely pyrophoric and must not be allowed to come into contact with the atmosphere. This reagent should only be handled by individuals trained in its proper and safe use. It is recommended that transfers be carried out by using a 20-mL or smaller glass syringe filled to no more than 2/3 capacity, or by cannula. For a discussion of procedures for handling air-sensitive reagents, see Aldrich Technical Bulletin AL-134. [Note added August 2009]
A.
6,6'-Bi(3,4-dihydro-2H-pyran)
(Bis-DHP)
(Note 1). A 500-mL, two-necked flask (Flask A) equipped with a magnetic stirrer is flushed with dry argon and then charged with
30 mL of dry distilled 3,4-dihydro-2H-pyran (329 mmol) and
60 mL of dry tetrahydrofuran (THF)
(Note 2). Stirring is begun and the solution is cooled to −78°C by means of external cooling. An inert argon atmosphere is maintained throughout the reaction.
tert-Butyllithium
in pentanes (200 mL of a 1.7 M solution, 340 mmol) is added dropwise under argon and the resultant cloudy mixture is stirred at 0°C (ice/water bath) for 1 hr. Meanwhile, another 1-L flask (Flask B) equipped with a magnetic stirrer is flushed with dry argon (an inert argon atmosphere is again maintained throughout the reaction) and then charged with
2.0 g of palladium(II) chloride bis(acetonitrile) complex (2.2 mol%, 7.4 mmol),
46.3 g of copper(II) chloride (344 mmol) and
300 mL of dry THF. Stirring is initiated and the slurry is cooled to 0°C by means of external cooling. When the slurry has reached 0°C, the clear pale yellow solution from Flask A is added via cannula to cooled Flask B at 0°C. The orange brown slurry becomes black and the resultant mixture is stirred at 0°C for 1 hr. An aqueous saturated ammonium chloride / concentrated ammonium hydroxide solution (4:1, pH 10) is added to quench the reaction and the solution is extracted with
ether (3 × 200 mL). The combined ether extracts are dried over
magnesium sulfate
(MgSO4), filtered and concentrated under reduced pressure to give a yellow solid. This is purified by column chromatography on silica gel (Merck 9385, 6 cm × 20 cm) eluting with
1%
triethylamine / 5%
ether / 94%
petroleum ether
to yield 15.0 g of
6,6'-bi(3,4-dihydro-2H-pyran)
(Bis-DHP) as a white crystalline solid (55%) (Note 3) and (Note 4).
B.
Methyl 2,3-O-(6,6'-octahydro-6,6'-bi-2H-pyran-2,2'-diyl)-α-D-galactopyranoside
. A 100-mL, two-necked flask equipped with a magnetic stirrer, condenser and heating mantle is flushed with dry argon and then charged with
2.8 g of methyl α-D-galactopyranoside (14.4 mmol),
50 mL of dry chloroform
and
5.0 g of Bis-DHP (30.1 mmol)
(Note 5) and (Note 6). The solution is maintained under an argon atmosphere and
0.14 g of
DL-camphorsulfonic acid (0.6 mmol) is added. The mixture is heated under reflux for 1.5 hr. After this time,
4.6 mL of anhydrous ethylene glycol (83.3 mmol)
(Note 7) is added and heating is continued for a further 0.5 hr. The heating mantle is removed and the solution cooled to room temperature. The resultant solution is diluted with
100 mL of dichloromethane
, made basic by the addition of
potassium carbonate
(approximately 0.5 g required), filtered and concentrated under reduced pressure. The crude material is purified by column chromatography on silica gel (Merck 9385, 6 cm × 30 cm) eluting with
80-100%
ethyl acetate/petroleum ether
to yield 3.3 g of
methyl 2,3-O-(6,6'-octahydro-6,6'-bi-2H-pyran-2,2'-diyl)-α-D-galactopyranoside
as an off-white foam (64%) (Note 8).
2. Notes
1.
6,6'-Bi(3,4-dihydro-2H-pyran), 98% (Bis-DHP) is commercially available from Aldrich Chemical Company, Inc., P.O. Box 355, Milwaukee, WI 53201, USA. Catalog # 34,973-9.
2.
Because of the sensitivity of the reagents toward moisture, both procedures A and B should be carried out in oven-dried glassware under dry and inert conditions.
3.
Pure
bis(dihydropyran) is a white and relatively stable crystalline solid. As would be expected for an enol ether, it is sensitive to hydrolysis and is best stored for a long time under an inert atmosphere at −10°C.
4.
Physical data for purified material are as follows: mp
49-50°C (
petroleum ether);
1H NMR (270 MHz, CDCl
3) δ: 1.78-1.87 (m, 4 H), 2.08-2.14 (m, 4 H), 4.01-4.05 (m, 4 H), 5.16 (t, 2 H, J = 3.8)
;
13C NMR (68 MHz, CDCl
3) δ: 20.2, 22.4, 66.2, 96.8, 147.6
; m/z (EI) 166 (M
+), 138, 111, 83, 55
. Anal. calcd for C
10H
14O
2: C, 72.26; H, 8.49. Found C, 72.24; H, 8.56.
5.
The checkers have found that the
chloroform must be distilled prior to use to obtain an optimum yield.
6.
Although
toluene can be used for these reactions, boiling
chloroform is preferred. The use of more polar solvents such as
dimethylformamide (DMF) or
acetonitrile fail to give any products, presumably because of the competitive decomposition of the
bis-(dihydropyran). When the solubility of the starting material in boiling
chloroform is poor, reaction yields can be improved by applying ultrasound.
7.
By-products from this reaction include protection of the primary hydroxyl group and incorporation of only one Bis-DHP ring. These products are less stable than the desired product and may be deprotected on reaction with
ethylene glycol making purification of the reaction mixture much more efficient.
8.
Physical data for dispiroketal (dispoke) protected material are as follows:
[α]
D
23 −19.0 (
c 1.05 in CHCl
3);
1H NMR (270 MHz, CDCl
3) δ: 1.42-1.62 (m, 8 H), 1.65-1.85 (m, 4 H), 2.59 (br s, 1 H), 2.84 (br s, 1 H), 3.42 (s, 3 H), 3.55-3.75 (m, 4 H), 3.80-4.00 (m, 3 H), 4.05-4.15 (m, 2 H), 4.23 (dd, 1 H, J = 10.3, 3.4), 4.85 (d, 1 H, J = 3.4)
; m/z (EI) 360 (M
+), 200, 167 (C
10H
15O
2+
), 149, 111, 100
. Anal. calcd for C
17H
28O
8: C, 56.65; H, 7.83. Found C, 56.42; H, 8.01.
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.
3 This protection has now been simplified by the introduction of the dispiroketal (dispoke) group
4,5 and the cyclohexane diacetal (CDA) protecting group.
6 Regiocontrol, in the form of protection of the diequatorial vicinal diol pairs over axial-equatorial or diaxial systems occurs as a result of the stabilizing influence of multiple anomeric effects. Thus a general method for the protection of the diequatorial vicinal diols in a wide range of monosaccharides has been developed (Table 1). In only a few cases when steric interactions are of a lesser magnitude is some cis-diol protection noticed. O-Methyl, S-ethyl or O-pentenyl groups are tolerated at the C-1 carbon of the sugar with the more lipophilic groups enhancing the yields of dispiroketal protection. This reflects the greater solubility of these derivatives in
chloroform.
TABLE I
PROTECTION FOR DIEQUATORIAL VICINAL DIOLS
|
|
Sugar
|
3,4-Protection
|
2,3-Protection
|
|
|
|
0%
|
76%
|
|
|
62%
|
0%
|
|
|
45%
|
0%
|
|
|
0%
|
64%
|
|
|
40%
|
58%
|
|
|
47%
|
32%
|
|
|
26%
|
42%
|
|
For protection of glucose derivatives, which possess two sets of 1,2-trans diequatorial diols, protection is best achieved by way of
chiral
bis(dihydropyrans).
7 In this way, complete regioselectivity can be achieved as a result of chirality "matching" of the C-2, C-3 diol pairs with that of the
bis(dihydropyran).
The dispiroketal group is stable toward a variety of reaction conditions, including mild acid, and is compatible with glycosidic coupling reactions regardless of whether it is present on the donor or acceptor moiety.
5 When applied to sugar chemistry, the dispoke moiety can be employed as both a protecting group and a handle for tuning the reactivity of the sugar. This has allowed the concise syntheses of complex oligosaccharides to be achieved.
8 Finally, the facile cleavage of the dispiroketal unit can be accomplished with
95%
trifluoroacetic acid
at room temperature.
5
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Methyl 2,3-O-(6,6'-octahydro-6,6'-bi-2H-pyran-2,2'-diyl)-α-D-galactopyranoside:
α-D-Galactopyranoside, methyl, 2,3-O-(octahydro[2,2'-bi-2H-pyran]-2,2'-diyl-, [2(2R,2'R)]- (13); (144102-32-9)
6,6'-Bi(3,4-dihydro-2H-pyran) [Bis-DHP]:
6,6'-Bi-2H-pyran, 3,3',4,4'-tetrahydro- (12); (109669-49-0)
3,4-Dihydro-2H-pyran:
2H-Pyran, 3,4-dihydro- (8,9); (110-87-2)
tert-Butyllithium:
Lithium, tert-butyl- (8);
Lithium, (1,1-dimethylethyl)- (9); (594-19-4)
Palladium(II) chloride bisacetonitrile: ALDRICH:
Bis(acetonitrile)dichloropalladium(II):
Palladium, bis(acetonitrile)dichloro- (8,9); (14592-56-4)
Copper(II) chloride:
Copper choride (8,9); (7447-39-4)
Methyl α-D-galactopyranoside:
α-D-Galactopyranoside, methyl (8,9); (3396-99-4)
(±)-Camphorsulfonic acid:
Boranesulfonic acid, 2-oxo-, (±)- (8);
Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (±)- (9); (5872-08-2)
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