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Synlett 2010(6): 869-872  
DOI: 10.1055/s-0029-1219560
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

exo-Glycals: Intermediates in the Synthesis of 1,1-Disubstituted C-Glycosides

Hannah Woodwarda, Nichola Smithb, Timothy Gallagher*a
a School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax: +44(117)9251295; e-Mail: t.gallagher@bristol.ac.uk;
b Novartis Institute for Biomedical Research, Novartis Horsham Research Centre, Horsham RH12 5AB, UK
Further Information

Publication History

Received 4 January 2010
Publication Date:
02 March 2010 (online)

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Abstract

The synthesis of 1,1-disubstituted C-glycosides containing amino and ester containing moieties at what is formally the anomeric site is described. Petasis olefination of pyranosyl lactones provided exo-glycals which underwent regioselective azidoselenation and subsequent radical-mediated C-glycoside formation.

Key words

C-glycosides - azidoselenation - Petasis olefination

    References and Notes

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5

Using C1-metalated endo-glycals we have prepared a series of C1-substituted alkyl and aryl glycals (i.e., 1 R = Alk, Ar) and evaluated these as substrates for azidoselenation. Even under forcing conditions, no azidoselenation was observed and this is attributed to the known (and facile) reversible nature of the azidoselenation process. We assume that trapping with Ph2Se2 of the intermediate (a tertiary or benzylic anomeric radical) resulting from initial N3˙addition is slow and expulsion of N3˙(and its subsequent decompo-sition) is too efficient. When the C1 substituent carried a pendent alkenyl residue (e.g., allyl), only addition to this less electron-rich alkene was observed (Gallagher, T.; Wang, J.-W. unpublished work).

8

Data for exo -Glycals
Conventional carbohydrate numbering (cf. sialic acids) is used.
Compound 8b: ¹H NMR (400 MHz, CDCl3): δ = 1.13, 1.20, 1.23, 1.28 [36 H, 4 × s, 4 × COC(CH3)3], 3.99-4.10 (2 H, m, H7a + H7b), 4.25 (1 H, m, H6), 4.50 (1 H, t, J = 1.5 Hz, =CHH, H1a), 4.77 (1 H, t, J = 1.5 Hz, =CHH, H1b), 5.15 (1 H, dd, J = 10.5, 3.0 Hz, H4), 5.53 (1 H, dd, J = 3.0, 1.0 Hz, H5), 5.76 (1 H, dt, J = 10.5, 1.5 Hz, H3). ¹³C NMR (100 MHz, CDCl3): δ = 27.0, 27.1, 38.7, 38.8, 61.2, 66.6, 67.2, 71.5, 75.8, 95.3, 154.6, 176.7, 176.8, 177.8. ESI-HRMS: m/z calcd for C27H4409 [M + Na]+: 535.2878; found: 535.2868. Compound 9: ¹H NMR (400 MHz, CDCl3): δ = 1.14-1.24 [36 H, m, 4 × COC(CH3)3], 3.77-3.78 (1 H, m, H6), 4.06-4.26 (2 H, m, H7a + H7b), 4.49 (1 H, t, J = 1.5 Hz, H1a), 4.80 (1 H, t, J = 1.5 Hz, H1b), 5.26 (2 H, dd, J = 7.0, 2.5 Hz, H4 + H5), 5.47 (1 H, m, H3). ¹³C NMR (100 MHz, CDCl3): δ = 27.1, 27.2, 38.8, 38.9, 61.7, 67.6, 69.0, 72.8, 76.6, 96.2, 154.0, 176.4, 176.5, 177.1, 178.1. ESI-HRMS: m/z calcd for C27H4409 [M + Na]+: 535.2878; found: 535.2902.
Compound 10: ¹H NMR (400 MHz, CDCl3): δ = 1.13-1.25 [36 H, m, 4 × COC(CH3)3], 3.87 (1 H, m, H6), 4.23-4.25 (2 H, m, H7a + H7b), 4.71 (1 H, d, J = 1.0 Hz, H1a), 4.83 (1 H, d, J = 1.0 Hz, H1b), 5.15 (1 H, dd, J = 10.0, 3.5 Hz, H4), 5.62 (1 H, app t, J = 10.0 Hz, H5), 5.69 (1 H, d, J = 3.5 Hz, H3). ¹³C NMR (100 MHz, CDCl3): δ = 27.0, 27.1, 27.1, 38.7, 38.8, 38.9, 61.4, 64.5, 68.9, 71.0, 77.0, 101.4, 152.9, 176.6, 176.9, 177.3, 178.1. ESI-HRMS: m/z calcd for C27H44O9
[M + Na]+: 535.2877; found: 535.2890.

9

To determine whether the carbohydrate substrates were reactive towards Pd(0), a series of control experiments were carried using cinnamyl acetate as a standard. Exposure of cinnamyl acetate and exo-glycal 8b (or 9 or 10) to sodio-diethyl malonate in the presence of a catalytic quantity of Pd(0) (Pd2dba3/dppe) led to the expected substituted cinnamyl adduct as the only product observed and galacto 8b was recovered unchanged. With the gluco substrates 9 essentially the same outcome was observed: cinnamyl acetate reacted but exo-glycal 9 did not. In the case of the manno variant 10, and under the same reaction conditions, none of the cinnamyl substitution product was detected, suggesting that coordination of Pd(0) to 10 occurred [to sequester Pd(0)] but any resulting complex (e.g., 11) was then unreactive towards the external malonate nucleophile.

11

Extensive attempts (varying ligands, reaction temperatures, solvents and catalysts, including use of palladium and nickel) to carry out the allylic displacement chemistry using manno substrate 10 were all unsuccessful.

12

Spectroscopic data are provided for the galacto series shown in Scheme  [4] .
Compound 13: ¹H NMR (400 MHz, CDCl3): δ = 1.12-1.28 [36 H, m, 4 × COC(CH3)3], 3.12 (1 H, d, J = 13.5 Hz, 1 × CH2N3), 3.62 (1 H, d, J = 13.5 Hz, 1 × CH2N3), 3.94 (1 H, dd, J = 11.0, 9.0 Hz, H6a), 4.03 (1 H, dd, J = 11.0, 6.0 Hz, H6b), 4.71 (1 H, m, H5), 5.48 (1 H, dd, J = 10.5, 3.0 Hz, H3), 5.59 (1 H, dd, J = 3.0, 1.0 Hz, H4), 5.87 (1 H, d, J = 10.5 Hz, H2), 7.35-7.44 (3 H, m, ArCH), 7.58-7.61 (2 H, m, ArCH). ¹³C NMR (100 MHz, CDCl3): δ = 26.9, 27.0, 27.1, 38.7, 38.8, 38.9, 39.0, 56.1, 60.3, 66.5, 66.7, 70.5, 70.5, 91.9, 124.5, 129.3, 137.6, 176.3, 177.9, 180.4, 180.5. ESI-HRMS: m/z calcd for C33H49N3O9Se [M + Na]+: 734.2526; found: 734.2556.
Compound 14: ¹H NMR (400 MHz, CDCl3): δ = 1.11-1.27 [36 H, m, 4 × COC(CH3)3], 2.09 (3 H, s, NHCOCH 3), 3.36 (1 H, dd, J = 14.5, 3.5 Hz, 1 × CH 2NHCOCH3), 3.97 (1 H, m, H6a), 4.06-4.15 (2 H, m, H6b + 1 × CH 2NHCOCH3), 4.85 (1 H, m, H5), 5.50-5.53 (2 H, m, H2 + H4), 5.61 (1 H, m, H3), 6.03 (1 H, m, NH), 7.31-7.38 (3 H, m, ArCH), 7.59-7.64 (2 H, m, ArCH). ¹³C NMR (100 MHz, CDCl3): δ = 20.7, 26.9, 27.0, 27.1, 27.2, 27.2, 38.7, 38.8, 39.0, 45.0, 60.4, 66.4, 67.1, 70.2, 71.1, 91.6, 124.7, 129.1, 129.2, 129.2, 137.4, 169.3, 176.4, 177.2, 177.9, 178.1. ESI-HRMS: m/z calcd for C35H53NO10Se [M + Ma]+: 750.2727; found: 750.2712.
Compound 15: ¹H NMR (300 MHz, CDCl3): δ = 1.11-
1.30 [36 H, m, 4 × COC(CH3)3], 1.40-1.55 [2 H, m, CH2CH 2CO2C(CH3)3], 2.06 (3 H, s, NHCOCH 3), 2.17-
2.32 [2 H, m, CH 2CH2CO2C(CH3)3], 3.38-3.44 (2 H, m, CH 2NHCOCH3), 3.62 (1 H, m, H5), 3.97-4.04 (2 H, m, H6a + H6b), 5.08 (1 H, dd, J = 10.5, 3.0 Hz, H4), 5.20 (1 H, d, J = 10.0 Hz, H2), 5.48 (1 H, dd, J = 10.0, 3.0 Hz, H3), 6.05 (1 H, d, J = 5.0 Hz, NH). ¹³C NMR (100 MHz, acetone-d 6): δ = 20.2, 23.5, 26.5, 26.6, 26.7, 26.8, 27.1, 27.5, 27.5, 27.6, 27.6, 38.4, 38.8, 39.5, 42.5, 61.3, 66.5, 67.8, 72.5, 77.0, 106.9, 172.1, 172.9. ESI-HRMS: m/z calcd for C36H61NO12 [M + Na]+: 722.4086; found: 722.4098.
Compound 18: ¹H NMR (300 MHz, acetone-d 6): δ = 1.09-1.22 [36 H, m, 4 × COC(CH3)3], 1.44-1.49 [2 H, m, CH2CH 2CO2C(CH3)3], 2.01 (3 H, s, NHCOCH 3), 2.40-2.42 (2 H, m, CH 2CH2CO2C(CH3)3), 3.26 (1 H, dd, J = 14.5, 4.5, 1 × CH 2NHCOCH3), 3.43 (1 H, dd, J = 14.5, 7.5, 1 × CH 2NHCOCH3), 4.02 (1 H, m, H5), 4.09-4.11 (2 H, m, H6a + H6b), 5.00 (1 H, app t, J = 10.0 Hz, H4), 5.17 (1 H, d, J = 10.0 Hz, H2), 5.49 (1 H, app t, J = 10.0 Hz, H3), 6.42 (1 H, br s, NH). ¹³C NMR (100 MHz, acetone-d 6): δ = 20.2, 23.3, 26.5, 26.6, 26.7, 27.5, 27.0, 27.6, 29.5, 29.3, 42.4, 62.7, 68.6, 70.1, 71.2, 104.1, 169.2, 172.0, 176.8, 177.3, 177.3. ESI-HRMS: m/z calcd for C36H61NO12 [M + Na]+: 722.4086; found: 722.4109.
Compound 21: ¹H NMR (400 MHz, acetone-d 6): δ = 1.10-1.29 [36 H, m, 4 × COC(CH3)3], 1.44-1.50 [2 H, m, CH2CH 2CO2C(CH3)3], 2.12 (3 H, s, NHCOCH 3), 2.29-
2.32 [2 H, m, CH 2CH2CO2C(CH3)3], 3.22 (1 H, m, 1 × CH 2NHCOCH3), 3.40 (1 H, m, 1 × CH 2NHCOCH3), 3.90 (1 H, m, H5), 4.12 (1 H, dd, J = 12.0, 4.5 Hz, H6a), 4.24 (1 H, d, J = 12.0, 2.0 Hz, H6b), 5.14 (1 H, dd, J = 10.0, 3.5 Hz, H3), 5.36 (1 H, d, J = 10.0 Hz, H2), 5.41 (1 H, dd, J = 3.5, 1.0 Hz, H4). ¹³C NMR (100 MHz, acetone-d 6): δ = 20.0, 26.4, 26.5, 26.6, 26.7, 27.0, 27.5, 27.6, 27.7, 38.3, 38.5, 39.0, 42.0, 42.3, 61.9, 65.6, 68.1, 72.4, 76.2, 100.0, 173.2, 176.9, 177.1, 179.8. ESI-HRMS: m/z calcd for C36H61NO12 [M + Na]+: 722.4086; found: 722.4087.

15

Compound 22: ¹H NMR (400 MHz, acetone-d 6): δ = 1.06, 1.10, 1.16, 1.26 [36 H, 4 × s, 4 × COC(CH3)3], 1.97 (NHCOCH 3), 3.53 (1 H, dd, J = 15.0, 5.0 Hz, 1 × CH 2NHCOCH3), 3.74 (1 H, dd, J = 15.0, 8.0 Hz, 1 × CH 2NHCOCH3), 4.09 (1 H, m, H5), 4.16 (1 H, dd, J = 12.0, 4.5 Hz, H6a), 4.32 (1 H, dd, J = 12.0, 2.0 Hz, H6b), 4.67 (1 H, d, J = 12.0 Hz, 1 × CH2Ph), 4.90 (1 H, d, J = 12.0 Hz, 1 × CH2Ph), 5.37 (1 H, app t, J = 2.0 Hz, H2), 5.44-5.46 (2 H, m, H3 + H4), 6.16 (1 H, app t, J = 6.0 Hz, NH), 7.35 (1 H, m, ArCH), 7.40-7.48 (4 H, m, ArCH). ¹³C NMR (100 MHz, CDCl3): δ = 20.3, 26.5, 26.5, 26.6, 26.8, 37.7, 38.3, 38.5, 38.6, 38.7, 59.7, 61.6, 62.7, 65.0, 68.1, 70.1, 101.4, 127.7, 127.8, 128.7, 138.0, 170.0, 176.3, 176.6, 177.1, 177.3. ESI-HRMS: m/z calcd for C36H55NO11 [M + Na]+: 700.3667; found: 700.3679
Compound 23: ¹H NMR (400 MHz, CDCl3): δ = 1.12, 1.14, 1.25, 1.30 [36 H, 4 × s, 4 × COC(CH3)3], 3.26 (1 H, d, J = 13.5 Hz, 1 × CH2N3), 3.70 (1 H, d, J = 13.5 Hz, 1 × CH2N3), 3.92 (1 H, app dq, J = 10.0, 2.0 Hz, H5), 4.12
(1 H, app d, J = 3.5 Hz, H6a), 4.14 (1 H, app d, J = 3.5 Hz, H6b), 4.62 (2 H, ABq, J = 12.0 Hz, CH 2Ph), 5.41-5.52 (2 H, m, H3 + H4), 5.58 (1 H, d, J = 3.0 Hz, H2), 7.35-7.45 (5 H, m, ArCH). ¹³C NMR (100 MHz, CDCl3): δ = 27.0, 27.1, 38.3, 38.8, 49.5, 61.8, 63.3, 64.7, 68.4, 70.1, 70.6, 100.8, 127.2, 128.7, 131.5, 136.4, 176.7, 177.1, 178.0. ESI-HRMS: m/z calcd for C34H51N3O11 [M + Na]+: 684.3467; found: 684.3478.