Zinc-Mediated Synthesis of α-C-Glycosides from 1,2-Anhydroglycosides

Abstract

α-C-Glycosides have been prepared by the addition of organozinc reagents to glycal epoxides. Dialkyl and diaryl zinc reagents in the presence of CF₃COOH provide the corresponding α-glycosides in 53-82% yields. Organozinc chlorides RZnCl formed by the reaction RLi with zinc chloride can also be successfully applied to this coupling reaction with high α-selectivity.

α-C-glycosides - epoxide - organozinc reagents - stereoselectivity - trifluoroacetic acid

References

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<A NAME="RU03403ST-1B">1b</A> Postema MHD. C-Glycoside Synthesis   CRC Press; Boca Raton: 1995. 

For recent review of C-glycosides see:

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<A NAME="RU03403ST-10">10</A>

General Procedure for Preparation of α- C -Glycosides. To a solution of tri-O-benzyl-d-glucal (42 mg, 0.1 mmol) and 1.5 mL of CH₂Cl₂ at 0 °C was added a solution of dimethyldioxirane (0.15 mmol) in actone dropwise. After stirring for 30 min, the reaction mixture was concentrated in vacuum. The resulting white solid was taken up in CH₂Cl₂ (1.0 mL). To another solution of ZnR₂ (0.2 mmol, 2 equiv) in 1 mL of CH₂Cl₂ at 0 °C was added CF₃COOH (15 µL, 0.2 mmol, 2 equiv) very slowly via syringe under N₂. After stirring for 30 min, to this solution was added the solution of epoxide dropwise via syringe. The mixture was stirred for 3-5 h from 0 °C to r.t. The reaction was quenched with sat. aq NH₄Cl and extracted with CH₂Cl₂ (3 ¥ 10 mL). The combined organic solution was washed with brine, dried (MgSO₄), and concentrated. Then, the product was isolated by silica gel column chromatography. Acetylated 3a: Mp 55-56 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.33-7.27 (m, 13 H), 7.16 (m, 2 H), 5.05 (dd, J = 8.8, 5.5 Hz, 1 H), 4.77 (d, J = 11.5 Hz, 1 H), 4.74 (d, J = 9.5 Hz, 1 H), 4.71 (d, J = 11.2 Hz, 1 H), 4.63 (d, J = 12.2 Hz, 1 H), 4.52 (d, J = 10.3 Hz, 1 H), 4.50 (d, J = 10.9 Hz, 1 H), 4.02 (m, 1 H), 3.82 (m, 1 H), 3.71-3.65 (m, 4 H), 1.99 (s, 3 H), 1.70 (m, 1 H), 1.48 (m, 1 H), 0.94 (t, J = 7.4 Hz, 3 H). ¹³C NMR (400 MHz, CDCl₃): δ = 170.1, 138.4, 138.2, 138.0, 128.4, 128.3, 128.0, 127.8, 127.7, 127.6, 80.2, 77.7, 74.7, 74.6, 73.7, 73.5, 73.1, 71.6, 69.0, 20.9, 19.1, 9.6. HRMS (FAB⁺) calcd for C₃₁H₃₆O₆: 505.2590 [MH⁺]. Found: 505.2585. Acetylated 3e: Mp 62-63 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.33-7.26 (m, 13 H), 7.15 (m, 2 H), 5.05 (dd, J = 8.6, 5.3 Hz, 1 H), 4.76 (d, J = 11.5 Hz, 1 H), 4.74 (d, J = 10.4 Hz, 1 H), 4.71 (d, J = 9.8 Hz, 1 H), 4.61 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 10.8 Hz, 1 H), 4.11 (m, 1 H), 3.82 (m, 1 H), 3.72-3.65 (m, 4 H), 3.51 (t, J = 6.6 Hz, 2 H), 1.99 (s, 3 H), 1.80-1.77 (m, 3 H), 1.55 (m, 1 H), 1.43-1.40 (m, 2 H). ¹³C NMR (400 MHz, CDCl₃): δ = 170.1, 138.4, 138.1, 137.9, 129.7, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 80.0, 77.5, 74.7, 74.6, 73.5, 72.9, 71.9, 68.9, 44.8, 32.2, 25.4, 22.6, 20.9. HRMS (FAB⁺) calcd for C₃₃H₃₉O₆Cl: 567.2513 [MH⁺]. Found: 567.2500. Acetylated 3f: Mp 77-78 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.27-7.10 (m, 13 H), 7.10 (m, 2 H), 4.98 (dd, J = 8.7, 5.4 Hz, 1 H), 4.71 (d, J = 11.8 Hz, 1 H), 4.67 (d, J = 10.7 Hz, 1 H), 4.65 (d, J = 11.1 Hz, 1 H), 4.55 (d, J = 12.1 Hz, 1 H), 4.46 (d, J = 11.9 Hz, 1 H), 4.44 (d, J = 10.9 Hz, 1 H), 4.09-3.94 (m, 3 H), 3.74 (m, 1 H), 3.66-3.59 (m, 4 H), 1.96 (s, 3 H), 1.93 (s, 3 H), 1.71-1.51 (m, 4 H), 1.47-1.26 (m, 2 H). ¹³C NMR (400 MHz, CDCl₃): δ = 171.2, 170.1, 138.4, 138.2, 138.1, 128.5, 128.4, 128.1, 127.9, 127.8, 127.7, 127.6, 80.1, 77.6, 74.8, 74.7, 73.6, 73.1, 72.1, 72.0, 69.0, 64.3, 29.8, 28.4, 25.7, 21.8, 21.0. HRMS (FAB⁺) calcd for C₃₅H₄₂O₈: 591.2958 [MH⁺]. Found: 591.2952. Acetylated 3h: Mp 70-71 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.38 (m, 2 H), 7.29-7.19 (m, 16 H), 7.08 (m, 2 H), 5.13 (d, J = 5.7 Hz, 1 H), 4.91 (dd, J = 9.9, 5.7 Hz, 1 H), 4.81-4.71 (m, 3 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.48 (d, J = 10.8 Hz, 1 H), 4.46 (d, J = 12.3 Hz, 1 H), 3.98 (m, 2 H), 3.71-3.63 (m, 3 H), 1.96 (s, 3 H). ¹³C NMR (300 MHz, CDCl₃): δ = 170.2, 138.7, 138.2, 138.1, 132.1, 128.6, 128.5, 128.2, 128.1, 127.9, 127.8, 122.3, 89.6, 83.2, 81.4, 77.9, 75.5, 75.4, 74.2, 73.7, 72.8, 68.8, 66.3, 21.1. IR (KBr): ν = 2909, 2228, 1741, 1454, 1238, 1099, 1041 cm^-1. HRMS (FAB⁺) calcd for C₃₇H₃₆O₆: 599.2409 [MNa⁺]. Found: 599.2408.

<A NAME="RU03403ST-11A">11a</A>

The stereochemistry of α-C-glycosides was assigned from the coupling constants, which J _1,2 value ranged from 4.2 to 5.9 Hz.

<A NAME="RU03403ST-11B">11b</A> Leeuwenburgh MA. Timmers CM. van der Marel GA. van Boom JH. Mallet JM. Sinay PG. Tetrahedron Lett.  1997,  38:  6251 

<A NAME="RU03403ST-11C">11c</A>

See ref. [6b]

For trifluoracetic acid accelerated the cyclopropanation of olefins, see:

<A NAME="RU03403ST-12A">12a</A> Yang Z. Lorenz JC. Shi Y. Tetrahedron Lett.  1998,  39:  8621 

<A NAME="RU03403ST-12B">12b</A> Charette AB. Lacasse MC. Org. Lett.  2002,  4:  3351 

<A NAME="RU03403ST-13">13</A> For ZnCl₂ mediated sodium malonate addition to glycal epoxides with β-selectivity, see: Timmers CM. Dekker M. Buijsman RC. van der Marel GA. Ethell B. Anderson G. Burchell B. Mulder GJ. van Boom JH. Bioorg. Med. Chem. Lett.  1997,  7:  1501 

<A NAME="RU03403ST-14">14</A>

For ZnCl₂ mediated acetylide anion additions to glycal epoxides with α-selectivity, see ref. [11a]

<A NAME="RU03403ST-15">15</A>

For comparison, the reaction of n-butylmagnesium chloride with epoxide 2 in THF from -78 °C to 0 °C gave a 45:55 mixture of α- and β-C-glycoside.