Stereoselective Synthesis of α- and β-C-Glycosides by Addition of Titanium Enolates to Glycals

Abstract

Both α- and β-C-glycosides can be prepared by SnCl₄-mediated addition of titanium enolates from N-acetylthiazolidine­thiones to glycals. Subsequent removal of the chiral auxiliary provides enantiomerically pure fragments that are useful for the synthesis of natural products.

Key words

stereoselective reactions - C-glycosidations - titanium enolates - glycals - thiazolidinethiones

References and Notes

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• 6 As occurs in the greater part of C-glycosidation methodo-logies, those described in reference 5 are unable to provide both stereochemistries from a single glycosyl donor. For an exception, see: Allwein SP. Cox JM. Howard BE. Johnson HWB. Rainier JD. Tetrahedron  2002,  58:  1997 
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1

Current address: School of Biological and Chemical Sciences, Queen Mary University of London, Joseph Priestley Building, Mile End Road, London E1 4NS, UK

10

The α- and β-stereochemistry of C-glycosides was established through NMR studies, involving NOESY experiments that uncovered diagnostic interactions (Figure  [¹] ).

Figure 1

11

Representative procedure: Neat TiCl₄ (0.12 mL, 1.1 mmol) was added dropwise to a solution of 2 (203 mg, 1.0 mmol) in CH₂Cl₂ (8 mL), at 0 ˚C under N₂. The yellow suspension was stirred for 5 min at 0 ˚C, cooled to -78 ˚C, and a solution of i-Pr₂NEt (0.19 mL, 1.1 mmol) in CH₂Cl₂ (1.5 mL) was added. The dark-red enolate solution was stirred for 30 min at -78 ˚C and 2 h at -50 ˚C. Then, 1 M SnCl₄ in CH₂Cl₂ (1.1 mL, 1.1 mmol) followed by tri-O-acetylgalactal (a; 136 mg, 0.5 mmol) in CH₂Cl₂ (1.5 mL) were successively added dropwise at -78 ˚C. The resulting mixture was stirred at -78 ˚C for 30 min and kept at -20 ˚C for 72 h. The reaction was cooled at -78 ˚C and quenched by the addition of saturated NH₄Cl (6 mL) with vigorous stirring. The layers were separated, the aqueous layer was re-extracted with CH₂Cl₂, and the combined organic extracts were dried (Na₂SO₄), filtered and concentrated. Analysis of the resultant oil by HPLC and ^¹H NMR showed the presence of a single diastereomer. The product was then purified by column chromatography on deactivated (2.5% Et₃N) silica gel (CH₂Cl₂-EtOAc, 95:5), to afford β-C-glycoside 6a (159 mg, 0.38 mmol, 76% yield) as a viscous yellow oil. R _f = 0.7 (CH₂Cl₂-EtOAc, 95:5). [α]_D -181 (c 0.9, CHCl₃). IR (film): 2964, 1738, 1699, 1369, 1235, 1170, 1044 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.08 (dd, J = 10.0, 1.2 Hz, 1H, CH=CHCHOAc), 6.03 (ddd, J = 10.0, 4.9, 2.0 Hz, 1 H, CH=CHCHOAc), 5.16-5.11 (m, 1 H, NCH), 5.10-5.06 (m, 1 H, CHOAc), 4.75-4.68 (m, 1 H, OCHCH=CH), 4.22-4.16 (m, 2 H, CH₂OAc), 3.92 (td, J = 6.4, 2.4 Hz, 1 H, OCHCH₂OAc), 3.60-3.46 (m, 3 H, SCH_xH_y and COCH₂), 3.04 (dd, J = 11.6, 1.2 Hz, 1 H, SCH_xH_y), 2.44-2.32 [m, 1 H, CH(CH₃)₂], 2.08 (s, 3 H, CH₃CO), 2.06 (s, 3 H, CH₃CO), 1.07 (d, J = 6.8 Hz, 3 H, CH₃), 0.99 (d, J = 6.8 Hz, 3 H, CH₃). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 202.9, 170.7, 170.6, 170.4, 135.1, 123.2, 73.8, 71.7, 71.6, 63.8, 62.8, 43.3, 30.8 (×2), 21.0, 20.8, 19.1, 17.8. HRMS (+FAB): m/z [M + H]⁺ calcd for C₁₈H₂₆NO₆S₂: 416.1202; found: 416.1200.

14

Adducts 9 and 10 were isolated in low yields because of the sensitivity of the 1,3-thiazolidine-2-thione auxiliary. Yields reported in Table  [²] were not optimized.