A novel and expeditious approach to the stereoselective synthesis of 2- S-ethyl(phenyl)-2-deoxy-β-glycosides, ready precursors to 2-deoxy-β- glycosides

Article abstract of DOI:10.1016/S0040-4039(00)00281-1

1,2-Migration and concurrent glycosidation of ethyl(phenyl) 2,3- orthoester-1-thio-α-L-rhamnopyranosides under the action of TMSOTf readily afforded the corresponding 2-S-ethyl(phenyl)-2-deoxy-β-glycosides, ready precursors to 2-deoxy-β-glycosides. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00281-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2961–2964
A novel and expeditious approach to the stereoselective synthesis
of 2-S-ethyl(phenyl)-2-deoxy-β-glycosides, ready precursors to
2-deoxy-β-glycosides
Biao Yu ∗ and Zunyi Yang
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 4 January 2000; accepted 14 February 2000
Abstract
1,2-Migration and concurrent glycosidation of ethyl(phenyl) 2,3-orthoester-1-thio-α-L-rhamnopyranosides un-
der the action of TMSOTf readily afforded the corresponding 2-S-ethyl(phenyl)-2-deoxy-β-glycosides, ready
precursors to 2-deoxy-β-glycosides. © 2000 Elsevier Science Ltd. All rights reserved.
2-Deoxy-β-glycosides exist as important structural components in many natural products, such as
macrolides, anthracyclines, cardiac glycosides, aureolic acids, and enediynes.1 However, the synthesis of
the 2-deoxy-β-glycosidic linkage has been found to be one of the most challenging tasks in glycosylation
reactions.2 The most extensively developed strategy for the synthesis of 2-deoxy-β-glycosides utilizes
donors with equatorial C-2 heteroatom substituents (e.g., -Br, -I, -SR, -SePh, -NHCHO, and -OAc),2,3
which act as directing groups and are removed after the glycosylation event. The preparation of
these donors often requires specialized methods. We report herein an expeditious approach to the
stereoselective synthesis of 2-S-ethyl(phenyl)-2-deoxy-β-glycosides, ready precursors to 2-deoxy-β-
glycosides.
The results surprised us when we attempted to glycosylate thioglycoside acceptor 1 with glycosyl
trichloroacetimidate donor 2: the corresponding coupling product was produced in 64% yield under
the promotion of BF3·OEt2 (0.1 equiv.) at low temperature (−78°C);4 however, the main product
isolated was found to be 3 (70% yield) when TMSOTf (0.15 equiv.) was used as the promoter and at
a higher temperature (−10°C) (Scheme 1).5 We envisaged that the production of 3 should involve the
glycosylation of 1 with 1,2-episulphonium ion C, which resulted from the oxycarbenium ion B, and
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00281-1
tetl 16561

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B from orthoester A (Scheme 1). Bundle and Auzanneau have reported that treatment of ethyl 2,3-
orthoester-1-thio-α-L-rhamnopyranoside with p-TsOH resulted in the 1,2-ethylthio group migration.6
Nicolaou et al. have demonstrated the preparation of 2-S-phenylglycosyl fluoride from phenyl 2-
hydroxyl-1-thioglycoside through 1,2-migration under the action of DAST.7 1,2-Migration was also
directly utilized to prepare 2-S-ethyl(phenyl)glycosides employing ethyl(phenyl) thioglycosides with a
phenoxythiocarbonyl ester on C-2 as donor and NIS/TfOH as promoter.8 Recognizing that the present
disclosure might provide an expeditious and convenient alternative to the synthesis of 2-deoxy-β-
glycosides, we sought to extend the scope of this reaction. Some preliminary results are listed in Table
1.
Scheme 1.
As expected on mechanistic grounds (Scheme 1), in the absence of the trichloroacetimidate 2, the
1,2-migrated self-coupled product 3 was still produced in a comparable yield (64%) (entry 1). When an
alcohol acceptor (diosgenin, 1.5 equiv.) was added to the reaction, the glycosidation product of diosgenin
(8) was isolated in 19% yield, whereas the self-coupling product 3 turned out to be the major ‘byproduct’
(entry 2). Therefore, the readily accessible 2,3-orthoester 4 was prepared9 and used instead as the donor
in the reaction. Treatment of 4 with diosgenin, cyclohexanol, cholesterol, as well as with sugar alcohols
6 and 7 (0.15 equiv. TMSOTf, rt) produced the expected 2-S-ethyl-β-glycosides (8–12) in moderate to
good yields (39–68%); the corresponding α-anomers were not detected (entries 3–7).10,11 The anomeric
ethylthio ether on acceptor 6 was unaffected (entry 6). However, the resulting -OEt from the 2,3-
orthoester of donor 4 competed considerably with the alcohol acceptors for the glycosidation reactions,
producing the corresponding ethyl 3-O-acetyl-4-O-benzoyl-2,6-deoxy-2-S-ethyl-β-L-glucopyranoside
(15) in 20–53% yields. It is known that Raney nickel mediated desulfurization of the SEt derivative
is less facile than that of the corresponding SPh derivative.3c,8 Therefore, phenyl 2,3-orthoester-1-thio-
α-L-rhamnopyranoside 5 was prepared9 and used as a donor (entries 8 and 9). The reactions of phenyl
1-thioglycoside 5 with sugar alcohols 6 and 7 (0.2 equiv. TMSOTf, room temperature, 0.5 h) provided
the corresponding 2-S-phenyl-2-deoxyglycoside 13 and 14 in 53 and 43% yields, with the OEt transfer
product 16 in 32 and 38% yields, respectively.
Although the expected 2-S-ethyl(phenyl)glycosides were produced in only moderate to good yields
due to the OEt transfer side reaction in this protocol, it should be noted that the yields for the expected
glycosides (8–14) were calculated based on the 2,3-orthoester donors (4 and 5) added (1.2 equiv.). The

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Table 1
Expeditious synthesis of 2-S-ethyl(phenyl)-β-glycosides10,11
yields would be excellent if they were calculated on the consumed acceptors and the latter calculation
would be reasonable in the synthesis of 2-deoxy-β-glycoside containing natural products in which the
aglycone is precious (e.g., antibiotics) and the preparation of the orthoester donors (4 and 5) is very
convenient.9 Improvement of this novel protocol and its application to other sugar donors and to the
synthesis of biologically important 2-deoxy-glycosides are in progress and will be reported in due course.

2964
Acknowledgements
We thank the Ministry of Science and Technology of China and the National Natural Science
Foundation of China (29925203) for financial support and Mr. Hai Yu for technical assistance.
References
1. Kirsching, A.; Bechtold, A. F.-W.; Rohr, J. Top. Curr. Chem. 1997, 188, 1.
2. For reviews, see: (a) Boons, G.-J. Contemporary Organic Synthesis 1996, 173. (b) Toshima, K.; Tatsuta, K. Chem. Rev.
1993, 93, 1503.
3. For the latest successful examples, see: (a) Roush, W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1, 891. (b) Roush, W.
R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541. (c) Roush, W. R.; Hartz, R. A.; Gustin, D. J. J. Am. Chem. Soc. 1999,
121, 1990.
4. Yu, B.; Yu, H.; Hui, Y.; Han, X. Synlett 1999, 753.
5. At −78°C, little 1 was consumed. Therefore, the reaction temperature was raised to −10°C; at and above this temperature 3
was produced as the major product.
6. Auzanneau, F.-I.; Bundle, D. R. Carbohydr. Res. 1991, 212, 13.
7. Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A. J. Am. Chem. Soc. 1986, 108, 2466.
8. (a) Zuurmond, H. M.; van der Klein, P. A. M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1992, 33, 2063. (b)
Zuurmond, H. M.; van der Klein, P. A. M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron 1993, 49, 6501.
9. 2,3-Orthoester 4 (or 5) was readily prepared from ethyl (or phenyl) 1-thio-α-L-rhamnopyranoside by two routes. Route 1: (1)
CH3C(OEt)3 (2.5 equiv.), p-TsOH (cat.), DMF, rt, 1.5 h; (2) BzCl, Py, rt; ∼46% for two steps. Route 2: (1) CH3C(OMe)2CH3,
p-TsOH (0.03 equiv), CH2Cl2, rt; (2) BzCl, Py, rt; (3) 80% HOAc, 75°C, 3 h; (4) CH3C(OEt)3 (1.5 equiv.), p-TsOH (cat.),
CH2Cl2, rt, 1.0 h; ∼89% for four steps.
10. A typical procedure was as follows: To a stirred solution of cholesterol (101 mg, 0.313 mmol) in anhydrous CH2Cl2 (2 mL)
at room temperature under argon was added a solution of TMSOTf in CH2Cl2 (0.1 M, 0.39 mmol) followed by the addition
of a solution of orthoester 4 (100 mg, 0.26 mmol) in CH2Cl2 (0.5 mL). After being stirred for 1 h, the mixture was filtered,
concentrated, and applied to a silica gel column (petroleum ether:EtOAc, 8:1) to give 10 (142 mg, 68%) and 15 (28 mg,
25%) as white solids.
1
11. All new compounds exhibited satisfactory H NMR, MS, and elemental analytical data. The indicated stereochemistry
at C-1 and C-2 of the 2-S-ethyl(phenyl)glycosyl moiety in the products (3, 8–16) was expected on mechanistic grounds
1
1
and determined by H NMR data. The H NMR signals (300 MHz, CDCl3) for H-1 and H-2 of the corresponding 2-S-
ethyl(phenyl)-β-gluco- residue were characteristic: Compound 3: 4.46 (1H, d, J=8.7 Hz, H-1), 2.73–2.52 (5H, m, H-2,
2×SCH2CH3). Compound 8: 4.57 (1H, d, J=8.7 Hz, H-1), 2.80–2.63 (3H, m, H-2, SCH2CH3). Compound 9: 4.54 (1H, d,
J=8.8 Hz, H-1), 2.79–2.61 (3H, m, H-2, SCH2CH3). Compound 10: 4.42 (1H, d, J=8.9 Hz, H-1), 2.80–2.60 (3H, m, H-2,
SCH2CH3). Compound 11: 4.62 (1H, d, J=8.8 Hz, H-1), 2.83–2.48 (5H, m, H-2, 2×SCH2CH3). Compound 12: 4.45 (1H,
d, J=8.9 Hz, H-1), 2.80–2.60 (3H, m, H-2, SCH2CH3). Compound 13: 4.69 (1H, d, J=9.1 Hz, H-1), 3.40 (1H, dd, J=8.8,
11.3 Hz, H-2). Compound 14: 4.41 (1H, d, J=8.8 Hz, H-1), 3.18 (1H, dd, J=8.8, 11.2 Hz, H-2). Compound 15: 4.50 (1H, d,
J=8.7 Hz, H-1), 2.80–2.63 (3H, m, H-2, SCH2CH3). Compound 16: 4.36 (1H, d, J=8.8 Hz, H-1), 3.18 (1H, dd, J=8.8, 11.3
Hz, H-2).