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

Hannah Woodward; Nichola Smith; Timothy Gallagher

doi:10.1055/s-0029-1219560

LETTER

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

Hannah Woodward^a, Nichola Smith^b, 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

Abstract

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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

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References and Notes

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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alkenyl residue (e.g., allyl), only addition to this less electron-rich alkene was observed (Gallagher, T.; Wang, J.-W. unpublished work).

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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.

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.

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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.

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.

An X-ray diffraction experiment on 16 was carried out at 100 K on a Bruker APEX II diffractometer using MoKα radiation (λ = 0.71073 Å). The data collection was performed using a CCD area detector from a single crystal mounted on a glass fibre. Intensities were integrated (Bruker-AXS SAINT V7.60A) from several series of exposures measuring 0.5˚ in ω or φ. Absorption corrections were based on equivalent reflections using SADABS (Sheldrick, G. M. SADABS V2008/1, University of Göttingen, Germany), and structures were refined against all F_o ^² data with hydrogen atoms riding in calculated positions using SHELXL Bruker-AXS SAINT V7.60A.^¹³b The Cambridge Crystallographic Data Centre deposition number for 16 is CCDC 763564.

<A NAME="RD00210ST-13B">13b</A> Sheldrick GM. Acta Crystallogr., Sect. A 2008, 64: 112

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<A NAME="RD00210ST-14B">14b</A> Mehta S. Pinto BM. J. Org. Chem. 1993, 58: 3269

<A NAME="RD00210ST-14C">14c</A> Demchenko A. Synlett 2003, 1225

<A NAME="RD00210ST-14D">14d</A> France RR. Compton RG. Davis BG. Fairbanks AJ. Rees NV. Wadhawan JD. Org. Biomol. Chem. 2004, 2: 2195

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.