Org. Synth. 1995, 72, 1
DOI: 10.15227/orgsyn.072.0001
L-(S)-GLYCERALDEHYDE ACETONIDE
[1,3-Dioxolane-4-carboxaldehyde, 2,2-dimethyl-, (S)-]
Submitted by Christian Hubschwerlen, Jean-Luc Specklin, and J. Higelin
1.
Checked by Todd M. Heidelbaugh and Leo A. Paquette.
1. Procedure
A 500-mL, four-necked, reaction flask, equipped with a mechanical stirrer, thermometer, and glass pH electrode combined with an automatic titrator (Note 1), is charged with sodium (meta)periodate (85.5 g, 0.4 mol) (Note 2) and water (200 mL). The suspension is cooled to 0°C in an ice bath and 3 N sodium hydroxide (about 133 mL, 0.4 mol) is added dropwise at a rate such that the temperature does not exceed 7°C. The final pH of the suspension is 5.5. The cooling bath is removed and finely powdered 5,6-O-isopropylidene-L-gulono-1,4-lactone (Note 3) (43.6 g, 0.2 mol) is added in one portion. The temperature of the mixture is kept below 30°C (Note 4). The pH of the suspension is maintained at 5.5 during the course of the reaction by addition of aqueous 15% sodium carbonate (about 15 mL). The suspension is further stirred at room temperature for 30 min, saturated with sodium chloride (105 g), and filtered by suction using a Büchner funnel. The white solid (Note 5) is washed thoroughly with two 50-mL portions of brine and the pH of the combined aqueous layers is adjusted to 6.7 with aqueous 15% sodium carbonate before extraction with dichloromethane (6 × 100 mL) (Note 6). The combined organic extracts are dried over magnesium sulfate (25 g). The magnesium sulfate is removed by filtration and washed with two 50-mL portions of dichloromethane. The organic solutions are combined and slowly concentrated to about 50 mL under reduced pressure (Note 7). The remaining solution is placed in a 100-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and a 10-cm, vacuum-jacketed, Claisen-Vigreux column (10-mm diameter). With constant stirring by a magnetic stirrer, the solution is further concentrated by distillation under reduced pressure (400 mbar) at 35°C (bath temperature) (Note 8). The temperature of the oil bath is then gradually increased to 80°C and the glyceraldehyde acetonide is distilled between 51°C and 52°C. The distillate is collected in a receiver cooled with an ice-methanol bath (Note 9). Approximately 14.5 g of L-(S)-glyceraldehyde acetonide (56% based on 5,6-O-isopropylidene-L-gulono-1,4-lactone) is obtained.
2. Notes
1.
A 200-mm Radiometer combined glass/reference electrode (Ag/AgCl) was used. To control the pH the submitters used a Radiometer standard pH meter PHM82 coupled to a TTT80 titrator. The end point was set to pH 5.5. If an automatic delivery system is not used the pH range should be kept between 4 and 6 during the oxidation process. Low pH values favor hydrolysis of the acetonide protective group, high pH values lead to epimerization of the aldehyde. The checkers did not use an automatic titrator. The pH was adjusted manually; 1.25 hr was required to bring the solution to pH 5.5.
2.
Sodium (meta)periodate (puriss. p.a.) was purchased from Fluka Chemical Corporation and used without any purification.
3.
5,6-O-Isopropylidene-L-gulono-1,4-lactone was purchased from Fluka Chemical Corporation and used without any purification. It can also be synthesized from
ascorbic acid in a two-step procedure.
24.
The temperature of the solution was kept between 20°C and 30°C by occasional cooling with an
ice-water bath.
5.
The white solid is mainly
sodium iodate and
sodium chloride.
6.
GLC analysis of a sample of the crude, aqueous solution indicates the presence of
95% of the theoretical amount of glyceraldehyde acetonide. This crude, aqueous solution can be used for further chemical transformations,
2 but was not stored for more than 6 hr at 0°C. GLC analysis of the aqueous layer after
dichloromethane extraction still indicates the presence of about
30% of the total amount of glyceraldehyde acetonide in the aqueous solution.
7.
The submitters used the following conditions:
rotatory evaporator bath temperature: 35°C, cooling water temperature: −5°C; pressure: 500 mbar.
8.
In the condenser, the cooling water was replaced by a methanol-ice mixture.
9.
(S)-Glyceraldehyde acetonide is an unstable liquid that starts to polymerize on standing even at low temperature. It can be depolymerized by distillation before use. The
1H NMR spectrum is as follows (CDCl
3) δ: 1.43 and 1.49 (2 s, 2 × 3 H), 4.08–4.21 (2 dd, 2 × 1 H, J = 4.4, 7.6), 4.38 (ddd, 1 H, J = 2, 4.4, 7.6), 9.72 (d, 1 H, J = 2), internal tetramethylsilane standard). The optical rotation is
[α]D20 −75.4° (
benzene,
c 8) [lit.
[α]D20 −67.9°/69.7° (
benzene,
c 8/2.2)
3,4].
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
Optically pure glyceraldehyde acetonides are widely used in the synthesis of enantiomerically pure compounds (EPC synthesis).
5 Whereas
D-(R)-glyceraldehyde acetonide is easily obtained from the inexpensive
D-mannitol,
6,7 there are only a limited number of practical syntheses of the enantiomeric
L-(S)-glyceraldehyde acetonide.
8,9 Difficulties arise from different sources: 1) availability of the starting material
diisopropylidene-L-mannitol; 2) length of the synthesis;
10 3) nature of the reactants used :
mercury acetate, mercaptans,
lead tetraacetate,
ozone at −78°C, 4) moderate yields.
11,12,13,14The procedure reported here is practical, uses readily available, non-toxic starting materials, and can be easily scaled up. No harmful by-products are formed during the synthesis, and
sodium iodate, generated during the periodate cleavage, can be recycled into
sodium metaperiodate.
15This preparation is referenced from:
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
brine
D-(R)-GLYCERALDEHYDE ACETONIDE
(S)-Glyceraldehyde acetonide
Benzene (71-43-2)
sodium hydroxide (1310-73-2)
sodium chloride (7647-14-5)
sodium carbonate (497-19-8)
mercury acetate (1600-27-7)
dichloromethane (75-09-2)
ozone (10028-15-6)
magnesium sulfate (7487-88-9)
sodium metaperiodate,
sodium (meta)periodate (7790-28-5)
sodium iodate (7681-55-2)
ascorbic acid
D-mannitol (69-65-8)
5,6-O-isopropylidene-L-gulono-1,4-lactone
L-(S)-Glyceraldehyde acetonide (22323-80-4)
1,3-Dioxolane-4-carboxaldehyde, 2,2-dimethyl-, (S)- (22323-80-4)
diisopropylidene-L-mannitol
lead tetraacetate (546-67-8)
Copyright © 1921-, Organic Syntheses, Inc. All Rights Reserved