Pyranyl Heterocycles from Inverse Electron Demand Hetero [4+2] Cyclo­addition Reactions of Chiral Allenamides as a New Chiral Template for Constructing C-Glycoside Substrates

Abstract

A useful sequence involving stereoselective functionalization of the two olefins in pyranyl heterocycles derived from inverse electron demand hetero [4+2] cycloadditions of chiral allenamides is described here. This sequence constitutes stereo­selectively dihydroxylation or hydroboration-oxidation of the steri­cally accessible C5 exocyclic olefin followed by hydroboration-oxidation of the endocyclic olefin at C2/C3. The ultimate success in the removal of the C6 chiral auxiliary completes the demonstration of the concept of employing these unique hetero cycloadducts as chiral templates for constructing highly functionalized pyrans or C-glycosides.

Key words

hetero [4+2] cycloadditions - pyranyl heterocycles - hydroboration-oxidation

References

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  Xiong, H.; Tracey, M. R.; Grebe, T. P.; Mulder, J. A.; Hsung, R. P. Org. Synth., 2003, accepted.

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1

A recipient of 2001 Camille Dreyfus Teacher-Scholar Award and McKnight Faculty Award.

10

For selected experimental procedures and characterizations:
9BBN Hydroboration-Oxidation of 5. To a solution of 29.0 mg of pyran 5 (0.071 mmol) in 3 mL of anhyd THF at r.t. was added 0.48 mL of 9BBN (2.5 equiv, 0.5 M solution in THF, 0.18 mmol). The resulting mixture was stirred at r.t. for 1 h, and was quenched with excess of 30% aq H₂O₂ and 15% aq NaOH via drop wise addition. After which, the reaction mixture was refluxed for 3 h. The solution was then cooled to r.t. and extracted with Et₂O (2 × 10 mL) and EtOAc (10 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Silica gel flash chromatography (60% EtOAc in hexanes) of the crude led to the desired alcohol 6 (22.2 mg, 73% yield).
6: R_f = 0.33 (60% EtOAc in hexanes); [α] _d ²⁰ = -95.5 (c 0.58, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.58 (ddd, J = 2.0, 12.0, 17.0 Hz, 1 H), 0.75 (d, J = 7.0 Hz, 3 H), 1.65 (ddd, J = 5.0, 9.0, 11.0 Hz, 1 H), 2.48 (m, 1 H), 2.72 (s, 3 H), 3.65 (m, 2 H), 3.89 (dq, J = 3.5, 9.0 Hz, 1 H), 4.64 (dd, J = 3.5, 11.0 Hz, 1 H), 4.73 (d, J = 9.0 Hz, 1 H), 4.90 (dd, J = 2.0, 6.0, Hz, 1 H), 6.31 (dd, J = 2.0, 4.0 Hz, 1 H), 7.10-8.30 (m, 12 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.9, 150.6, 138.0, 134.1, 133.8, 130.8, 129.1, 128.3, 128.0, 127.8, 126.3, 126.0, 125.8, 125.1, 101.8, 81.9, 62.9, 58.8, 58.2, 38.8, 28.5, 19.4, 15.0. IR (thin film): 3400 (m), 3058 (w), 2925 (s), 2890 (m), 1681 (s), 1640 (w), 1434 (m)cm^-1. MS (EI): m/z (% relative intensity) = 429.2(40) [M⁺], 411.1(100); m/z calcd for C₂₇H₂₉N₂O₃: 429.21782, found 429.21780.
OsO ₄ Dihydroxylation of 5. To a solution of 80.0 mg of pyran 5 (0.20 mmol) in 10 mL of anhyd CH₂Cl₂ at -78 °C were added 4.0 mL of TMEDA (0.27 mmol) and drop wise via a syringe a solution of 66.7 mg of OsO₄ [0.27 mmol] in 2 mL of CH₂Cl₂. After the solution was stirred for 30 min at -78 °C, it was carefully concentrated under reduced pressure. The resulting residue was dissolved in THF (10 mL) and H₂O (1 mL). After adding 2 g of NaHSO₃ to the crude mixture, the reaction mixture was refluxed at 75 °C for 12 h. The solution was then cooled to r.t., and extracted with EtOAc (3 × 15 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Silica gel flash column chromatography (80% EtOAc in hexanes) of the crude furnished the desired diol 10 (70.3 mg, 85% yield) as a thick colorless oil.
10: R_f = 0.32 (80% EtOAc in hexanes). [α] _d ²⁰ = -33.0 (c 0.60, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.76 (d, J = 6.5 Hz, 1 H), 1.05 (d, J = 17.5 Hz, 1 H), 1.80 (dd, J = 3.5, 17.5 Hz, 1 H), 2.72 (s, 3 H), 3.33 (t, J = 11.0 Hz, 1 H), 3.42 (brs, 1 H), 3.90 (dq, J = 7.0, 13.0 Hz, 1 H), 3.96 (dd, J = 3.5, 12.5 Hz, 1 H), 4.77 (d, J = 9.0 Hz, 1 H), 4.83 (dd, J = 2.5, 5.5 Hz, 1 H), 4.91 (dd, J = 3.5, 10.5 Hz, 1 H), 5.72 (s, 1 H), 7.20-8.4 (m, 12 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.4, 150.1, 137.5, 134.0, 133.7, 131.3, 129.1, 128.9, 128.5, 128.4, 128.1, 127.4, 126.5, 126.2, 126.0, 125.8, 124.9, 99.2, 85.0, 70.0, 66.1, 59.4, 57.9, 28.4, 14.8. IR (thin film): 3377 (s), 3053 (w), 2925 (s), 2854 (m), 1677 (s), 1440 (m) cm^-1. MS (EI): m/z (% relative intensity) = 445.2(90) [M⁺], 118.9(100); m/z calcd for C₂₇H₂₉N₂O₄: 445.21273. Found: 445.21270.
A General Procedure for BH ₃ Hydroboration Using 9. To a solution of 12.0 mg of the TBS ether 9 (0.022mmol) in anhyd THF (1 mL) at r.t. was added BH₃×THF (0.44 mL) complex (2.0 equiv, 1 M solution in THF, 0.044 mmol). The reaction mixture was stirred for 2 h at r.t., and was quenched carefully with drop wise addition of excess of 30% aq H₂O₂ and 15% aq NaOH. The mixture was then stirred vigorously for 30 min at r.t. The resultant mixture was extracted with Et₂O [2 × 5 mL] and EtOAc [5 mL], and the combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Silica gel flash chromatography (40% EtOAc in hexanes) of the crude provided alcohol 20 (7.40 mg, 60% yield) as a colorless oil.
20: R_f = 0.20 (40% EtOAc in hexanes). ¹H NMR (500 MHz, toluene-d ₈): δ = -0.01 (s, 3 H), 0.04 (s, 3 H), 0.34 (d, J = 6.5 Hz, 3 H), 1.00 (s, 9 H), 1.76 (ddd, J = 4.0, 11.5, 20.5 Hz, 1 H), 2.51 (s, 3 H), 2.62 (m, 1 H), 2.81 (dt, J = 4.0, 9.5 Hz, 1 H), 3.11 (dd, J = 6.0, 14.5 Hz, 1 H), 3.70 (dd, J = 5.5, 10.0 Hz, 1 H), 3.88 (t, J = 10.0 Hz, 1 H), 4.10 (m, 1 H), 4.46 (d, J = 8.5 Hz, 1 H), 5.05 (d, J = 9.0 Hz, 1 H), 5.87 (brs, 1 H), 7.01-8.45 (m, 12 H). ¹³C NMR (75 MHz, toluene-d ₈): δ = 162.5, 139.5, 135.7, 134.1, 132.4, 127.9, 127.6, 127.3, 127.4, 125.7, 125.3, 125.2, 125.0, 86.4, 82.9, 66.4, 60.2, 58.7, 57.2, 41.2, 33.2, 28.5, 25.8, 14.8, -5.5, -5.7 (missing 4 peaks due to overlap, and missing 1 additional peak). IR (thin film): 3377 (w), 3013 (w), 2954 (s), 2919 (s), 2848 (m), 1707 (m), 1507 (m), 1460 (s) cm^-1. MS (LCMS): m/z (% relative intensity) = 561.2 (10) [M⁺], 191 (100).
A General Procedure for Lewis Acid Mediated Allylation Using 20. To a solution of 5.0 mg of alcohol 20 (8.9 µmol) in 0.5 mL of anhyd CH₂Cl₂ at -78 °C were added 5.8 mg of SnBr₄ (1.5 equiv, 17.8 µmol) and 5.6 µL of allyltrimethylsilane (4 equiv, 35.6 µmol). The resultant mixture was warmed to r.t. and stirred for 12 h before it was quenched with sat. aq NH₄Cl (0.5 mL). The crude mixture was extracted with CH₂Cl₂ (3 × 5 mL) and the combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Silica gel flash chromatography (10% EtOAc in hexanes) of the crude furnished the desired pyran 21 (2.56 mg, 70% yield).
21: R_f = 0.35 (10% EtOAc in hexanes). [α] _d ²⁰ = +35.0 (c 0.20, CH₂Cl₃). ¹H NMR (500 MHz, toluene-d ₈): δ = -0.02 (s, 3 H), -0.01 (s, 3 H), 0.34 (s, 9 H), 1.02 (ddd, J = 5.5, 8.5, 14.5 Hz, 1 H), 1.78 (m, 2 H), 2.24 (ddd, J = 6.5, 7.5, 13.5 Hz, 1 H), 2.33 (ddd, J = 6.0, 8.5, 12.5 Hz, 1 H), 2.39 (d, J = 2.0 Hz, 1 H), 3.34 (dd, J = 6.0, 9.5 Hz, 1 H), 3.39 (dd, J = 4.5, 9.5 Hz, 1 H), 3.91 (m, 1 H), 4.33 (ddd, J = 3.0, 6.0, 15.0 Hz, 1 H), 5.05 (dd, J = 10.0, 20.5 Hz, 1 H), 5.66 (brs, 1 H), 5.96 (m, 1 H), 6.82-8.01 (m, 7 H). ¹³C NMR (75 MHz, toluene-d ₈): δ = 145.2, 141.8, 139.8, 131.0, 129.1, 127.8, 127.5, 127.4, 125.7, 125.4, 123.3, 82.5, 80.7, 79.6, 69.8, 64.5, 46.5, 40.2, 27.9, 25.7, -5.5, -5.7 (missing 1 signal). IR (thin film): 3430 (m), 3013 (w), 2941 (m), 2873 (m), 1640 (s), 1413 (m), 1149 (s) cm^-1. MS (EI): m/z (% relative intensity) = 413.1 (10) [M⁺ + H], 141.4 (45), 79.8 (100); m/z calcd for C₂₅H₃₆N₃O₃SiNa: 435.2331 [M⁺ + Na]. Found: 435.2344.
Periodic Cleavage of 24. To a solution of 30.0 mg of the triol 24 (0.064 mmol) in of MeOH/H₂O (5 mL, 5:1) at r.t. was added 69.0 mg of NaIO₄ (5 equiv, 0.32 mmol) and a drop of HOAc. The reaction mixture was stirred for 3 h at r.t. before it was concentrated and dissolved in EtOAc. The crude organic solution was washed with sat. aq Na₂S₂O₃ (3 mL) and H₂O. The aqueous layer was extracted with EtOAc (3 × 5 mL), and the combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Silica gel flash chromatography (80% EtOAc in hexanes) of the crude furnished the desired ketone 34 in 84% yield (23.0 mg).
34: R_f = 0.30 (80% EtOAc in hexanes). [α] _d ²⁰ = -61.0 (c 0.25, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.76 (d, J = 6.6 Hz, 3 H), 2.57 (dd, J = 6.3, 16.2 Hz, 1 H), 2.83 (s, 3 H), 3.33 (dd, J = 3.6, 16.2 Hz, 1 H), 3.92 (dq, J = 6.6, 8.7 Hz, 1 H), 4.48 (ddd, J = 4.2, 6.6, 10.2 Hz, 1 H), 4.90 (br s, 1 H), 5.14 (d, J = 9.0 Hz, 1 H), 5.34 (d, J = 4.5 Hz, 1 H), 7.20-8.25 (m, 12 H). ¹³C NMR (75 MHz, CDCl₃): δ = 193.8, 161.0, 137.1, 135.2, 128.7, 128.6, 128.4, 128.3, 128.2, 126.3, 125.8, 125.6, 124.2, 123.2, 84.0, 79.0, 71.0, 56.5, 44.5, 29.7, 14.2 (missing 4 peaks due to overlap, and missing 1 additional peak). IR (thin film): 3414 (m), 3047 (w), 2977 (s), 2875 (s), 1716 (s), 1681 (s) cm^-1. MS (LCMS): m/z (% relative intensity) = 431.1 (10) [M⁺], 413.1 (100).

11

When substituents at C5 and C6 are trans in these pyranyl heterocycles such as 21, we observed strong NOE between protons at C2 and C3 presumably because these two protons are not necessarily locked in di-axial relationship unlike those in pyrans where C5 and C6 substituents are cis.