Syntheses of Mono- and Divalent C-Aminoglycosides Using 1,2-Oxazine Chemistry and Olefin Metathesis

Abstract

An approach to mono- and divalent C-aminoglycosides starting from a new enantiopure 1,2-oxazine derivative is described. The introduction of a vinyl group into the 1,3-dioxolanyl substituent of a 1,2-oxazine allowed the Lewis acid promoted preparation of a vinyl-substituted bicyclic 1,2-oxazinone. After reduction of the carbonyl group, exhaustive hydrogenolysis provided branched C-aminoglycosides either with β-d-talose or β-d-idose configuration. The vinyl group of the protected rearrangement product 8 also allowed a self-metathesis with Grubbs II catalyst providing a ‘dimeric’ compound as an E/Z mixture. Its hydrogenolysis furnished the divalent C-aminoglycoside in good overall yield.

Key words

1,2-oxazine - pyran - C-glycoside - amino sugar - olefin meta­thesis - hydrogenation

• References and Notes

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• 22 Representative Experimental Procedures:(1R,5S,6S,8S,9R)-2-Benzyl-8-(hydroxymethyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonan-9-ol (7a) and (1R,5S,6S,8S,9S)-2-Benzyl-8-(hydroxymethyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonan-9-ol (7b): 1,2-Oxazine 2 (50 mg, 128 μmol) was dissolved in MeCN (2 mL) and cooled to 0 °C. Tin(IV) chloride (45 μL, 100 mg, 384 μmol) was added and the solution was stirred for 3 h at 0 °C, then additional tin(IV) chloride (45 μL, 100 mg, 384 μmol) was added and the reaction mixture was stirred for 18 h at r.t. H₂O (5 mL) was added and the aqueous layer was extracted with CH₂Cl₂ (5 × 10 mL). The combined organic layers were dried with Na₂SO₄, filtered and the solvent was removed in vacuo. The crude product was dissolved in EtOH (2 mL) and cooled to –30 °C. Sodium borohydride (10 mg, 256 μmol) was added and the suspension was stirred for 3 h at –30 °C. Then the solvent was removed in vacuo and the crude product was dissolved in CH₂Cl₂ (10 mL) and H₂O (5 mL) was added. The aqueous layer was extracted with CH₂Cl₂ (5 × 10 mL). The combined organic layers were dried with Na₂SO₄, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 1:4) to yield 7a (21 mg, 56%) and 7b(4 mg, 11%) as colorless solids.Data of 7a: mp 108–110 °C; [α]_D ²² +47.9 (c = 1.04, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.96 (m_c, 1 H, 5-H), 2.75 (br s, 1 H, OH), 3.11 (br s, 1 H, 1-H), 3.69, 3.73 (AB part of ABX system, J _AX = 4.6 Hz, J _BX = 6.6 Hz, J _AB = 11.0 Hz, 2 H, 8-CH₂), 3.70 (br s, 1 H, OH), 3.89 (br s, 1 H, 9-H), 3.99–4.03 (m, 1 H, 8-H), 4.09 (d, J = 14.1 Hz, 1 H, NCH₂), 4.16–4.18 (m, 1 H, 4-H), 4.17 (s, 1 H, 6-H), 4.19 (ddd, J = 0.6, 5.8, 12.1 Hz, 1 H, 4-H), 4.23 (d, J = 14.1 Hz, 1 H, NCH₂), 5.23 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.36 (br d, J = 17.4 Hz, 1 H, 2′-H), 5.84 (ddd, J = 4.7, 10.8, 17.4 Hz, 1 H, 1′-H), 7.27–7.34 (m, 5 H, Ph). ¹³C NMR (125 MHz, CDCl₃): δ = 39.1 (d, C-5), 62.1 (d, C-1), 62.2 (t, NCH₂), 63.8 (t, 8-CH₂), 65.1 (t, C-4), 70.4 (d, C-9), 78.7 (d, C-6), 79.3 (d, C-8), 116.6 (t, C-2′), 127.7, 128.6, 128.8 (3 × d, Ph), 135.9 (d, C-1′), 137.2 (s, Ph). IR (ATR): 3580–3180 (O–H), 3025–3005 (=C–H), 2930–2855 (C–H), 1595 (C=C), 1455 (C–H), 1230 (C–O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₆H₂₂NO₄: 292.1549; found: 292.1542; m/z [M + Na]⁺ calcd for C₁₆H₂₁NNaO₄: 314.1368; found: 314.1366.Data of 7b: mp 55–58 °C; [α]_D ²² +12.8 (c = 0.40, CHCl₃). ¹H NMR (700 MHz, CDCl₃): δ = 1.79 (m_c, 1 H, 5-H), 2.81 (m_c, 1 H, 1-H), 3.79, 3.98 (AB part of ABX system, J _AX = 4.0 Hz, J _BX = 5.4 Hz, J _AB = 11.6 Hz, 2 H, 8-CH₂), 4.11 (dd, J = 2.0, 12.1 Hz, 1 H, 4-H), 4.12 (d, J = 13.4 Hz, 1 H, NCH₂), 4.16–4.18 (m, 2 H, 4-H, 8-H), 4.27 (d, J = 13.4 Hz, 1 H, NCH₂), 4.62 (t, J = 4.0 Hz, 1 H, 9-H), 4.74 (dd, J = 1.5, 3.5 Hz, 1 H, 6-H), 5.24 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.42 (br d, J = 17.3 Hz, 1 H, 2′-H), 5.92 (ddd, J = 5.2, 10.8, 17.3 Hz, 1 H, 1′-H), 7.25–7.28, 7.31–7.34 (2 × m, 1 H, 4 H, Ph); signals for OH could not be detected. ¹³C NMR (175 MHz, CDCl₃): δ = 39.9 (d, C-5), 57.8 (t, NCH₂), 59.3 (d, C-1), 62.3 (d, C-9), 64.5 (t, C-4), 65.0 (t, 8-CH₂), 72.26 (d, C-6), 72.32 (d, C-8), 116.5 (t, C-2′), 124.9, 127.8, 128.7 (3 × d, Ph), 136.8 (d, C-1′), 136.9 (s, Ph). IR (ATR): 3425 (O–H), 3055–3030 (=C–H), 2950–2825 (C–H), 1645 (C=C), 1445 (C–H), 1250 (C–O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₆H₂₂NO₄: 292.1549; found: 292.1537; m/z [M + Na]⁺ calcd for C₁₆H₂₁NNaO₄: 314.1368; found: 314.1355. Anal. Calcd for C₁₆H₂₁NO₄ (291.3): C, 65.96; H, 7.27; N, 4.81. Found: C, 65.99; H, 7.22; N, 4.86.(1R,5R,6S,8S,9R)-2-Benzyl-9-(benzyloxy)-8-(benzyloxy-methyl)-6-vinyl-3,7-dioxa-2-azabicyclo[3.3.1]nonane (8): To a suspension of sodium hydride in mineral oil (15 mg, 60% NaH) in THF (1 mL) a solution of compound 7a (20 mg, 67 μmol) in THF (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1 h at r.t. and then cooled to 0 °C. Benzyl bromide (26 μL, 37 mg, 215 μmol) was added and the suspension was stirred for 18 h at r.t. The reaction was quenched with MeOH (1 mL) and the solvent was removed in vacuo. H₂O (5 mL) and EtOAc (10 mL) were added and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried with Na₂SO₄, filtered through a pad of Celite^® and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 20:1) to yield 8 (30 mg, 95%) as a colorless solid; mp 45–47 °C; [α]_D ²² +53.5 (c = 1.10, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.75 (m_c, 1 H, 5-H), 2.98 (br s, 1 H, 1-H), 3.53 (br t, J = 2.8 Hz, 1 H, 9-H), 3.58 (br d, J = 11.7 Hz, 1 H, 4-H), 3.64, 3.70, 3.79 (ABX system, J _BX = 5.2 Hz, J _AX = 8.8 Hz, J _AB = 11.8 Hz, 3 H, 8-CH₂, 8-H), 4.15 (m_c, 1 H, 6-H), 4.21 (d, J = 13.7 Hz, 1 H, NCH₂Ph), 4.36, 4.42 (AB system, J _AB = 11.8 Hz, 2 H, OCH₂Ph), 4.43 (td, J = 1.9, 11.7 Hz, 1 H, 4-H), 4.50 (d, s, J = 13.7 Hz, 3 H, NCH₂Ph, OCH₂Ph), 5.10 (br d, J = 10.8 Hz, 1 H, 2′-H), 5.26 (br d, J = 17.3 Hz, 1 H, 2′-H), 5.81 (ddd, J = 5.1, 10.8, 17.3 Hz, 1 H, 1′-H), 7.04–7.07, 7.09–7.20, 7.21–7.28 (3 × m, 1 H, 10 H, 4 H, Ph). ¹³C NMR (125 MHz, CDCl₃): δ = 37.4 (d, C-5), 55.2 (d, C-1), 57.6 (t, C-4), 58.4 (t, NCH₂Ph), 60.5 (t, OCH₂Ph), 70.5, 70.6 (2 × t, OCH₂Ph, 8-CH₂), 73.7 (d, C-9), 78.3 (d, C-8), 79.0 (d, C-6), 116.6 (t, C-2′), 127.0, 127.4, 127.7, 127.9, 128.0, 128.2, 128.4, 128.7, 128.8 (9 × d, Ph), 136.2 (d, C-1′), 138.1, 138.3, 138.9 (3 × s, Ph). IR (ATR): 3060–3025 (=C–H), 2930–2870 (C–H), 1645 (C=C), 1450 (C–H), 1240 (C–O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₀H₃₄NO₄: 472.2488; found: 472.2524; (ESI–TOF): m/z [M + Na]⁺ calcd for C₃₀H₃₃NNaO₄: 494.2307; found: 494.2345.(2S,3R,4S,5S,6S)-(3-Amino-6-ethyl-4-hydroxytetrahydro-2H-pyran-2,5-diyl)dimethanol (9b): A suspension of Pd/C (10% Pd, 70 mg) and i-PrOH (3 mL) was saturated with hydrogen for 15 min. To this suspension bicyclic compound 7b (70 mg, 240 μmol), dissolved in i-PrOH (1 mL), was added. The mixture was stirred for 18 h under hydrogen pressure (balloon). Then the mixture was filtrated through a pad of Celite^®, the solvent was removed in vacuo and the crude material was purified by column chromatography (silica gel; CH₂Cl₂–MeOH, 10:1) to yield 9b (34 mg, 69%) as a colorless solid; mp 143–145 °C; [α]_D ²² +63.1 (c = 1.02, MeOH). ¹H NMR (700 MHz, CD₃OD): δ = 0.77 (t, J = 7.4 Hz, 3 H, 2′-H), 1.39–1.45 (m, 1 H, 1′-H), 1.56–1.62 (m, 2 H, 5-H, 1′-H), 2.91 (br s, 1 H, 3-H), 3.15 (m_c, 1 H, 6-H), 3.20 (br s, 1 H, 2-H), 3.37, 3.47 (AB part of ABX system, J _AX = 5.6 Hz, J _BX = 6.7 Hz, J _AB = 11.5 Hz, 2 H, 2-CH₂), 3.44 (dd, J = 2.9, 11.4 Hz, 1 H, 5-CH₂), 3.60 (br d, J ≈ 11.4 Hz, 1 H, 5-CH₂), 3.80 (br t, J = 5.2 Hz, 1 H, 4-H). ¹³C NMR (175 MHz, CD₃OD): δ = 11.3 (q, C-2′), 26.3 (t, C-1′), 44.6 (d, C-5), 51.0 (d, C-3), 55.6 (t, 5-CH₂), 62.9 (t, 2-CH₂), 72.2 (d, C-4), 79.7 (d, C-2), 82.1 (d, C-6). IR (ATR): 3365–3300 (O–H, N–H), 2960–2845 (C–H), 1460 (C–H) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₉H₂₀NO₄: 206.1392; found: 206.1402; m/z [M + Na]⁺ calcd for C₉H₁₉NNaO₄: 228.1212; found: 228.1212.(E,1R,5R,6S,8S,9R)-1,2-Bis[2-benzyl-9-(benzyloxy)-8-(benzyl­oxymethyl)-3,7-dioxa-2-azabicyclo[3.3.1]nonan-6-yl]ethene (13a) and (Z,1R,5R,6S,8S,9R)-1,2-Bis-[2-benzyl-9-(benzyl­oxy)-8-(benzyloxymethyl)-3,7-dioxa-2-azabicyclo[3.3.1]-nonan-6-yl]ethane (13b): Benzyl-protected bicyclic compound 8 (300 mg, 636 μmol) was dissolved in degassed CH₂Cl₂ (5 mL). Grubbs II catalyst (18 mg, 21 μmol) was added to this solution and the mixture was stirred for 3 h at 40 °C. Then a second portion of Grubbs II catalyst (18 mg, 21 μmol) was added and after another 3 h of stirring at 40 °C a third portion of the catalyst (18 mg, 21 μmol) was added. The reaction mixture was stirred for 18 h at 40 °C. The solvent was removed in vacuo and the crude product was purified by column chromatography (silica gel; hexanes–EtOAc, 4:1) to yield 13a and 13b (165 mg, 57%, E-isomer; 117 mg, 40%, Z-isomer) as colorless oils.Data of E-isomer 13a: [α]_D ²² +66.1 (c = 1.04, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.95 (br s, 2 H, 5-H), 3.09 (br s, 2 H, 1-H), 3.66 (d, J = 1.9 Hz, 2 H, 9-H), 3.67 (d, J = 6.5 Hz, 2 H, 4-H), 3.77, 3.83, 3.90 (ABM part of ABMX system, J _MX = 5.2 Hz, J _BM = 6.4 Hz, J _AM = 8.8 Hz, J _AB = 11.6 Hz, 6 H, 8-H, 8-CH₂), 4.34 (br s, 2 H, 6-H), 4.39 (d, J = 13.5 Hz, 2 H, NCH₂Ph), 4.50, 4.56 (AB system, J _AB = 11.8 Hz, 4 H, OCH₂Ph), 4.53 (m_c, 2 H, 4-H), 4.58 (d, J = 13.5 Hz, 2 H, NCH₂Ph), 4.62, 4.65 (AB system, J _AB = 12.0 Hz, 4 H, OCH₂Ph), 5.96 (d, J = 1.5 Hz, 2 H, HC=CH), 7.20–7.36 (m, 20 H, Ph), 7.40–7.41 (m, 10 H, Ph). ¹³C NMR (125 MHz, CDCl₃): δ = 36.7 (d, C-5), 55.3 (d, C-1), 58.0 (t, C-4), 58.4 (t, NCH₂Ph), 70.5 (t, OCH₂Ph), 70.7 (t, 8-CH₂), 73.7 (t, OCH₂Ph), 76.1 (d, C-9), 77.9 (d, C-6), 78.3 (d, C-8), 127.1, 127.5, 127.7, 127.9, 128.2, 128.4, 128.7, 129.0 (8 × d, Ph), 129.3 (d, C=C), 138.1, 138.4, 138.8 (3 × s, Ph); one d for Ph could not be detected. IR (ATR): 3060–3030 (=C–H), 2920–2860 (C–H), 1735, 1660 (C=C), 1495 (C–H), 1240 (C–O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₅₈H₆₃N₂O₈: 915.4584; found: 915.4577; m/z [M + Na]⁺ calcd for C₅₈H₆₂N₂NaO₈: 937.4404; found: 937.4404. Anal. Calcd for C₅₈H₆₂N₂O₈ (915.1): C, 76.12; H, 6.83; N, 3.06. Found: C, 75.85; H, 7.20; N, 3.06.Data of Z-isomer 13b: [α]_D ²² +72.1 (c = 1.07, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 2.00 (m_c, 2 H, 5-H), 2.49 (s, 2 H, 1-H), 3.49 (t, J = 2.6 Hz, 2 H, 9-H), 3.58 (d, J = 11.8 Hz, 2 H, 4-H), 3.61, 3.70, 3.76 (ABM part of ABMX system, J _MX = 5.2 Hz, J _AM = 6.5 Hz, J _BM = 8.8 Hz, J _AB = 11.7 Hz, 6 H, 8-H, 8-CH₂), 4.23 (d, J = 13.7 Hz, 2 H, NCH₂Ph), 4.33, 4.38 (AB system, J _AB = 11.8 Hz, 4 H, OCH₂Ph), 4.44, 4.52 (AB system, J _AB = 11.8 Hz, 4 H, OCH₂Ph), 4.45–4.48 (m, 2 H, 4-H), 4.50 (d, J = 13.7 Hz, 2 H, NCH₂Ph), 4.54 (s, 2 H, 6-H), 5.65 (d, J = 3.6 Hz, 2 H, HC=CH), 7.05–7.27 (m, 30 H, Ph). ¹³C NMR (125 MHz, CDCl₃): δ = 36.9 (d, C-5), 55.4 (d, C-1), 57.7 (t, C-4), 58.4 (t, NCH₂Ph), 70.4 (t, OCH₂Ph), 70.8 (t, 8-CH₂), 73.7 (t, OCH₂Ph), 75.9 (d, C-9), 76.3 (d, C-6), 78.2 (d, C-8), 127.0, 127.4, 127.9, 128.0, 128.2, 128.5, 128.7, 128.8 (8 × d, Ph), 130.6 (d, C=C), 138.2, 138.3, 138.9 (3 × s, Ph); one d for Ph could not be detected. IR (ATR): 3085–3030 (=C–H), 2965–2855 (C–H), 1735, 1655 (C=C), 1495 (C–H), 1230 (C–O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₅₈H₆₃N₂O₈: 915.4584; found: 915.4585; m/z [M + Na]⁺ calcd for C₅₈H₆₂N₂NaO₈: 937.4404; found: 937.4407. Anal. Calcd for C₅₈H₆₂N₂O₈ (915.1): C, 76.12; H, 6.83; N, 3.06. Found: C, 75.33; H, 7.42; N, 3.06.Divalent C-Aminoglycoside 14: A suspension of Pd/C (10% Pd, 330 mg), MeOH (35 mL) and acetic acid (108 mg, 103 μL, 1.80 mmol) was saturated with hydrogen for 15 min. The bicyclic compound 13a (165 mg, 180 µmol) was dissolved in MeOH (2 mL), and added to the suspension. The mixture was stirred for 3 d under hydrogen pressure (balloon). The mixture was filtered through a pad of Celite^® and the solvent was removed in vacuo. The crude product was dissolved in MeOH (1 mL), hydroxylamine hydrochloride (55 mg, 791 μmol) was added and the reaction mixture was stirred for 30 min at 65 °C. The solvent was removed in vacuo, the crude product was dissolved in MeOH (0.5 mL) and EtOAc (0.5 mL) was added. The precipitated solid was filtered off, washed with EtOAc (3 × 1 mL) and dried in vacuo to yield 14 (41 mg, 60%; for numbering see Figure 1) as a brownish solid. Since the product is highly hygroscopic no melting point was determined.[α]_D ²² –5.0 (c = 0.60, MeOH). ¹H NMR (700 MHz, CD₃OD): δ = 1.71–1.76 (m, 2 H, CH₂), 1.98 (ddd, J = 1.6, 3.1, 5.9 Hz, 2 H, 5-H), 2.10–2.15 (m, 2 H, CH₂), 3.52 (dd, J = 1.5, 4.4 Hz, 2 H, 3-H), 3.63, 3.80, 3.85 (ABX part of ABXY system, J _XY = 1.5 Hz, J _AX = J _BX = 4.9 Hz, J _AB = 11.8 Hz, 6 H, 2-H, 2-CH₂), 3.69–3.70 (m, 2 H, 6-H), 3.88, 3.97 (AB part of ABX system, J _AX = 1.6 Hz, J _BX = 3.1 Hz, J _AB = 11.5 Hz, 4 H, 5-CH₂), 4.32 (dd, J = 4.4, 7.0 Hz, 2 H, 4-H). ¹³C NMR (175 MHz, CD₃OD): δ = 29.8 (t, CH₂), 44.0 (d, C-5), 52.3 (d, C-3), 55.2 (t, 5-CH₂), 63.2 (t, 2-CH₂), 68.9 (d, C-4), 77.0 (d, C-2), 80.3 (d, C-6). IR (ATR): 3310 (O–H, N–H), 2935 (C–H), 1235 (C–O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₆H₃₃N₂O₈: 381.2237; found: 381.2235; m/z [M + Na]⁺ calcd for C₁₆H₃₂N₂NaO₈: 403.2056; found: 403.2041.