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Synlett 2003(9): 1241-1246
DOI: 10.1055/s-2003-40352
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

C. Rameshkumar, Richard P. Hsung*
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, U.S.A.
e-Mail: hsung@chem.umn.edu;
Further Information

Publication History

Received 7 October 2002
Publication Date:
30 June 2003 (online)

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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

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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: Rf = 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: Rf = 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: Rf = 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: Rf = 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: Rf = 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.