A Lewis Acid Mediated Stereoselective Removal of an Anomeric Urea Substituent

Abstract

The first Lewis acid mediated stereoselective removal of an anomeric chiral urea group or an electron deficient nitrogen substituent is described here. The ability to remove this urea group which had served as a chiral auxiliary, along with stereoselective hydroboration-oxidation of the endocyclic olefin renders the pyran­yl cycloadduct from hetero [4+2] cycloadditions of chiral allen­amides a useful chiral template. This represents a new approach to synthesis of complex pyranyl heterocycles or C-glycoside derivatives.

Lewis acid - [4+2] cycloaddition - C-glycoside derivatives

References

1

A Recipient of 2001 Camille Dreyfus Teacher-Scholar Award. Author names are alphabetically ordered.

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6b

Xiong, H.; Tracey, M. R.; Grebe, T. P.; Mulder, J. A.; Hsung, R. P. Org. Synth. 2002, in press.

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12

The X-ray structure of pyran 8 is available in supplementary materials (Figure [1] ).

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16

For selected experimental procedures and characterizations:
General Procedure for Lewis Acid Mediated Allylations Using Pyran 8: To a solution of 317.7 mg of pyran 8 in 65 mL of freshly distilled CH₂Cl₂ at -78 °C under N₂ were added 503.9 mg of SnBr₄ (1.5 equiv, 1.16 mmol) and 0.488 mL of allyltrimethylsilane (4 equiv, 3.06 mmol). The reaction was vigorously stirred for 12 h and allowed to slowly warm to r.t. The solvent was removed under reduced pressure and purification using silica gel column chromatography afforded 157.6 mg of 9a and 9b as a mixture in addition to recovery of the Close’s auxiliary in 70-90% recovery range when attempted. The ratio of 9a:9b was found to be 4:1 from the crude ¹H NMR. Preparative thin layer chromatography (1% Et₂O in hexanes) was useful to separate the major isomer 9a from the minor isomer 9b.
9a (major). R_f = 0.30 (10% Et₂O in hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 1.06 (d, J = 7.0 Hz, 3 H), 1.70 (m, 1 H), 1.78 (m, 1 H), 2.03 (m, 2 H), 2.18 (m, 1 H), 2.47 (ddd, J = 1.0, 10.0, 18.0 Hz, 2 H) 3.43 (ddd, J = 6.0, 7.0, 7.0 Hz, 1 H), 4.96 (dd, J = 1.0, 10.0 Hz, 1 H), 5.04 (dd, J = 2.0, 15.0 Hz, 1 H), 5.52 (dd, J = 4.0, 8.0 Hz, 1 H), 5.74 (m, 1 H), 7.27-8.31 (m, 7 H). ¹³C NMR (125 MHz, C₆D₅CD₃): δ = 137.9, 135.8, 134.2, 128.8, 128.5, 127.8, 125.4, 125.2, 125.1, 124.8, 124.2, 115.6, 76.8, 69.6, 36.8, 32.2, 27.4, 27.3, 17.8. IR (thin film): 3052 (m), 2932 (m), 1641 (m) cm^-1. MS (EI): m/e (% relative intensity) = 266.2 (25) [M⁺], 249.6 (100). Optical rotation was not pursued because samples of 9a still contained some 9b.
9b (minor). R_f = 0.30 (10% Et₂O in hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 1.06 (d, J = 7.0 Hz, 3 H), 1.55 (m, 3 H), 1.74 (m, 1 H), 2.03 (m, 2 H), 2.65 (m, 1 H), 4.01 (dd, J = 4.0, 10.0 Hz, 1 H), 4.97 (d, J = 10.0 Hz, 1 H), 5.11 (d, J = 17.0 Hz, 1 H), 5.33 (dd, J = 1.0, 10.0 Hz, 1 H), 5.88 (m, 1 H), 7.07-8.25 (m, 7 H). ¹³C NMR (125 MHz, C₆D₅CD₃): δ = 136.0, 128.9, 128.8, 127.8, 127.5, 125.4, 123.8, 123.6, 115.7, 76.8, 68.1, 33.3, 32.6, 30.5, 27.6, 16.7 (3 signals are missing overlap with solvent). IR (thin film): 3064 (m), 2945 (m), 1635 (m)cm^-1. MS (EI): m/e (% relative intensity) = 284.2(50) [M + NH₄]⁺, 264.1(10), 247.1(100); m/e calculated for C₁₉H₂₆NO: 284.2015. Found: 284.2015.
General Procedure for Lewis Acid Mediated Allylations Using Pyran 20: To a solution of pyran 20 (5.0 mg, 0.011 mmol) in 1.0 mL of anhyd CH₂Cl₂ at -78 °C were added 7.63 mg SnBr₄ (1.5 equiv, 0.0174 mmol) and 7.50 µL of allyltrimethylsilane (4 equiv. 0.0464 mmol). The mixture was warmed to r.t. and stirred at r.t. for 12 h before it was quenched with sat. aq NH₄Cl (2 mL). The resultant mixture was extracted with CH₂Cl₂ (3 × 3 mL), and the combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Silica gel flash chromatography (gradient eluent: 0-10% EtOAc in hexanes) of the crude gave 2.32 mg (combined yield 70%) of pyran 21a and 22b with a 7:1 diastereomeric ratio.
Pyran 21a (major): R_f = 0.30 (10% EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 0.99 (d, J = 7.0 Hz, 3 H), 1.36 (ddd, J = 6.0, 12.0, 18.0 Hz, 1 H), 1.75 (dd, J = 12.0, 22.0 Hz, 1 H), 1.86 (m, 1 H), 2.27 (ddd, J = 6.5, 14.0, 15.0 Hz, 1 H), 2.42 (ddd, J = 4.5, 11.0, 16.5 Hz, 1 H), 2.71 (d, J = 1.5 Hz, 1 H), 3.68 (ddd, J = 4.5, 7.0, 15.5 Hz, 1 H), 4.46 (ddd, J = 3.5, 8.5, 15.5 Hz, 1 H), 5.13 (ddd, J = 9.5, 15.5, 17.5 Hz, 2 H), 5.84 (d, J = 2.0 Hz, 1 H), 5.94 (m, 1 H), 7.08-8.20 (m, 7 H). ¹³C NMR (75 MHz, CDCl₃): δ = 134.9, 128.7, 127.5, 125.8, 125.4, 125.2, 122.8, 122.6, 116.7, 86.0, 80.6, 69.7, 39.0, 38.5, 33.5, 16.2 (missing 3 peaks). IR (thin film): 3432 (s), 3072 (w), 3063 (w), 2971 (s), 2962 (s), 2953 (s) cm^-1. MS (EI): m/e (% relative intensity) = 282.2 (15) [M⁺], 125.1(100); m/e calcd for C₁₉H₂₂O₂: 282.1620. Found: 282.1618.
Pyran 21b (minor): R_f = 0.32 (10% EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 0.98 (d, J = 7.0 Hz, 3 H), 1.33 (ddd, J = 11.0, 20.5, 22.5 Hz, 1 H), 1.64 (dd, J = 5.5, 15.5 Hz, 1 H), 2.28 (m, 3 H), 2.82 (s, 1 H), 4.05 (ddd, J = 10.0, 13.0, 22.5 Hz, 1 H), 4.36 (ddd, J = 5.5, 10.5, 16.0 Hz, 1 H), 5.22 (m, 2 H), 5.82 (d, J = 4.5 Hz, 1 H), 5.98 (m, 1 H), 7.30-8.20 (m, 7 H). MS (EI): m/e (% relative intensity) = 282.2(15) [M⁺], 125.1(100); m/e calcd for C₁₉H₂₂O₂: 282.1620. Found: 282.1617.
Hydroboration Reactions: To a solution of 9.0 mg of pyran 16 (0.0218 mmol) in 2.0 mL of anhyd THF at r.t. was added 0.25 mL of BH₃⟨THF complex (2.5 equiv, 1 M solution in THF). The resultant mixture was stirred for 1 h and warmed to 55 °C for 1 h, and then, the mixture was cooled to r.t. and excess 30% aq H₂O₂ and 15% aq NaOH was added dropwise carefully. The resultant mixture was warmed to 60 °C for 10 min and vigorously stirred at r.t. for 1 h. The mixture was extracted with Et₂O (2 × 5 mL) and EtOAc (2 × 5 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Silica gel flash chromatography (50% EtOAc in hexanes) of the crude provided 6.62 mg of the desired alcohol 20 (70% yield) as a colorless oil.
Pyran 20: R_f = 0.35 (50% EtOAc in hexanes). [α] _d ²⁰ =
-77.0 (c 0.35, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.68 (d, J = 7.0 Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3 H), 2.01 (ddd, J = 3.5, 7.0, 10.0 Hz, 2 H), 2.25 (m, 1 H), 2.67 (s, 3 H), 3.72 (dq, J = 7.0, 8.5 Hz, 1 H), 4.02 (dd, J = 7.5, 16.0 Hz, 1 H), 4.84 (d, J = 8.0 Hz, 1 H), 5.04 (d, J = 9.0 Hz, 1 H), 5.63 (d, J = 2.0 Hz, 1 H), 7.20-8.41 (m, 12 H). ¹³C NMR (125 MHz, CDCl₃): δ = 162.5, 139.0, 134.9, 133.8, 131.7, 128.8, 128.5, 128.2, 127.5, 126.1, 125.7, 125.3, 125.0, 124.4, 86.3, 82.4, 67.3, 58.9, 57.1, 40.2, 32.6, 28.6, 15.1, 13.9 (missing 3 signals). IR (thin film): 3391 (m), 3029 (w), 2980 (w), 2930 (m), 2878 (m), 1684 (s), 1435 (m) cm^-1. MS (EI): m/e (% relative intensity) = 430.3(5) [M⁺], 273.2(100); m/e calcd for C₂₇H₃₀N₂O₃: 430.2256. Ffound: 430.2234.
Pyran 22 [C6-epimer]: R_f = 0.35 (50% EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 0.80 (d, J = 7.0 Hz, 3 H), 1.03 (d, J = 6.0 Hz, 3 H), 1.15 (ddd, J = 3.0, 5.0, 12.0 Hz, 1 H), 1.67 (dd, J = 12.0, 23.0 Hz, 1 H), 2.46 (m, 1 H), 2.81 (s, 3 H), 3.51 (ddd, J = 3.5, 5.0, 10.5 Hz, 1 H), 3.79 (dq, J = 6.5, 8.5 Hz, 1 H), 4.69 (d, J = 8.5 Hz, 1 H), 5.37 (d, J = 9.0 Hz, 1 H), 5.45 (d, J = 3.0 Hz, 1 H), 7.20-8.25 (m, 12 H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.6, 136.9, 134.9, 133.2, 128.6, 128.5, 128.3, 127.9, 127.8, 127.4, 125.6, 125.3, 125.1, 122.8, 90.9, 80.1, 68.4, 60.7, 55.7, 35.0, 32.2, 29.6, 28.5, 16.0, 14.5 (missing 2 peaks). MS (EI): m/e (% relative intensity) = 430.3 (5) [M⁺], 273.2 (100); m/e calcd for C₂₇H₃₀N₂O₃: 430.2256. Found: 430.2232.

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21

When substituents at C5 and C6 are trans in these pyranyl heterocycles, we observed strong NOE (see pyrans 21 and 22) between protons at C2 and C3 presumably because these two protons are not necessarily locked in a diaxial relationship unlike those in 20.