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Synlett 2009(4): 603-606  
DOI: 10.1055/s-0028-1087913
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Tandem One-Pot Acetalation-Acetylation for Direct Access to Differentially Protected Thioglycosides and O-Glycosides with p-Toluenesulfonic Acid

Kwok-Kong Tony Mong*, Chin-Sheng Chao, Min-Chun Chen, Chun-Wei Lin
Department of Applied Chemistry, National Chiao Tung University, 1001 Ta-Hsueh Road, Hsinchu 300, Taiwan
Fax: +886(3)5723764; e-Mail: tmong@mail.nctu.edu.tw;
Further Information

Publication History

Received 23 September 2008
Publication Date:
16 February 2009 (online)

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Abstract

A new tandem one-pot acetalation-acetylation procedure is reported which streamlines routine protecting-group manipulation of carbohydrate molecules in production of differentially protected O- and thioglycosides. This new procedure eliminates the use of highly toxic pyridine, and p-toluenesulfonic acid is employed as catalyst for acetalation and acetylation. Synthetic utility of the new procedure is demonstrated in the expeditious preparation of differentially protected glycosides from a wide variety of carbohydrate substrates including unprotected O-glycosides, thioglycosides, and N-acetyl neuraminic acid ester.

Key words

tandem - acetals - glycosides - oligosaccharides - protecting group

25

Unprotected thioglycosides 5-10 were derived from the corresponding peracetyl thioglycosides by Zemplèn deacetylation. Peracetyl thioglycosides were prepared by literature procedure reported in ref. 20.

27

Preparatory procedures of compounds 3 and 11 were described in supporting information.

30

General One-Pot Benzylidenation-Acetylation Procedure for the Preparation of 2 and 13-20
TsOH (10-32 mol%, Table  [¹] ) was added into a stirring mixture of carbohydrate substrate (1.0 equiv of methyl α-d-glucopyranoside, 3-8, 10, or 11) and PhCH(OMe)2 (1.5 equiv) in MeCN under N2. Upon complete conversion into benzylidene acetal intermediate as assessed by TLC, Ac2O (1.5 equiv per OH, total OH equals to the sum of OH of acetal intermediate plus MeOH released from acetalating reagent) was added, and the reaction temperature was brought up to 40 or 50 ˚C (Table  [¹] ). Specific reaction conditions are detailed in the supporting information. Upon complete acetylation as assessed by TLC, excess EtOAc
(4 × volume of MeCN used) was added to the mixture, which was then washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated for purification by flash column chromatography over SiO2. Elution with EtOAc-hexane mixture afforded the compounds 2 and 13-20.

31

General One-Pot Isopropylidenation-Αcetylation Procedure for Preparation of 21-24
TsOH (5-10 mol%, Table  [¹] ) was added into a stirring mixture of unprotected thioglycoside (1.0 equiv of 5, 6, 9, or NANA ester 12), and Me2CH(OMe)2 (1.5 equiv) in acetone. The mixture was stirred at r.t. or 40 ˚C under N2. Upon complete conversion into glycosyl ketal intermediate as assessed by TLC, Ac2O (1.5 equiv per OH, total OH equals to OH from glycosyl acetal intermediate plus MeOH released from acetalating reagent) was added, and the reaction temperature was brought up to 35 or 40 ˚C (Table  [¹] ). Specific reaction conditions for preparation of compounds 21-24 were detailed in the supporting information. Upon complete acetylation as assessed by TLC, excess EtOAc (4 × volume of MeCN used) was added to the mixture, which was then washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated for purification by flash column chromatography over SiO2. Elution with EtOAc-hexane mixture afforded compounds 21-24.

36

For acid-catalyzed one-pot acetalation-acetylation, unnecessary prolonged reaction time would compromise the yield of reaction due to the cleavage of the acetal function.