An Unexpected Reversal of Diastereoselectivity in the [4+3]-Cycloaddition Reaction of Nitrogen-Stabilized Oxyallyl Cations with Methyl 2-Furoate

Jennifer E. Antoline; Richard P. Hsung

doi:10.1055/s-2008-1042765

CLUSTER

An Unexpected Reversal of Diastereoselectivity in the [4+3]-Cycloaddition Reaction of Nitrogen-Stabilized Oxyallyl Cations with Methyl 2-Furoate

Jennifer E. Antoline, Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin-Madison, 777 Highland Avenue, Rennebohm Hall, Madison, WI 53705, USA
Fax: +1(608)2625345; e-Mail: rhsung@wisc.edu;

Abstract

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Abstract

An unexpected reversal of diastereoselectivity in the [4+3] cycloaddition of methyl 2-fuorate with nitrogen-stabilized oxyallyl cations derived from epoxidation of chiral allenamides is described here. This intriguing reversal in favor of the endo-II cycloaddition pathway is likely a result of minimizing the dipole interaction between the oxyallyl cation and ester carbonyl of methyl 2-fuorate.

Key words

stereoselective [4+3] cycloadditions - allenamides - nitrogen-stabilized oxyallyl cations - endo-I versus endo-II selectivity - dipole interaction

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Referenzen

References and Notes

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6 For a recent account that constitutes an enantioselective formal [4+3] cycloaddition, see: Dai X. Davies HML. Adv. Synth. Catal. 2006, 348: 2449

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8a Hsung RP. Wei L.-L. Xiong H. Acc. Chem. Res. 2003, 36: 773

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12 Rameshkumar C. Xiong H. Tracey MR. Berry CR. Yao LJ. Hsung RP. J. Org. Chem. 2002, 67: 1339

13 For our asymmetric [4+3] cycloaddition, see: Xiong H. Hsung RP. Berry CR. Rameshkumar C. J. Am. Chem. Soc. 2001, 123: 7174

14 Antoline JE. Hsung RP. Huang J. Song Z. Li G. Org. Lett. 2007, 9: 1275

15 Xiong H. Huang J. Ghosh SK. Hsung RP. J. Am. Chem. Soc. 2003, 125: 12694

Rameshkumar C. Hsung RP. Angew. Chem. Int. Ed. 2004, 43: 615

For a very recent account on intramolecular [4+3] cycloadditions of allenyl dienes employing PtCl₂ as a catalyst, see:

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18 Huang J. Hsung RP. J. Am. Chem. Soc. 2005, 127: 50

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General Procedure for the [4+3] Cycloaddition To a solution of the allenamide in CH₂Cl₂ [0.10 M] was added the appropriate furan (3.0-6.0 equiv) and 4 Å pulverized MS (0.50 g). The reaction solution was cooled to -78 °C, and ZnCl₂ (2.0 equiv, 1.0 M in Et₂O) was added. Then, DMDO in acetone (4.0-6.0 equiv) was added as a chilled solution (at -78 °C) via syringe pump over 3-4 h. The syringe pump was cooled by dry ice the entire addition time. After the addition the reaction mixture was stirred for another 14 h. The reaction was then quenched with sat. aq NaHCO₃, filtered through Celite^®, concentrated in vacuo, partitioned with CH₂Cl₂, extracted [4 × 20 mL], dried over Na₂SO₄, and concentrated in vacuo. The crude residue was purified via silica gel column chromatography (gradient eluent: 10-75% EtOAc in hexane).

20

In our intermolecular nitrogen stabilized oxyallyl cation [4+3] cycloadditions, for electron-rich furans, while some of the low-yielding reactions are due to decomposition of the epoxidized starting allenamide, most are due to noticeable competing epoxidation of the respective electron-rich furan. This issue can be circumvented using 6-10 equiv of furan, leading to higher yields (see references 13 and 18). For electron-deficient furans, the competing furan-epoxidation is not a problem, and thus, we can employ a much lower loading. However, we have found that reactions with electron-deficient furans such as those shown in this study are overall slower and more sluggish. This is consistent with the fact that oxyallyl cation based [4+3] cycloadditions proceed in an electrophilic manner.

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Analytical Data
Compound 4b: R _f = 0.10 (50% EtOAc in hexane); [α]_D ²³
-86.2 (c 0.10, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 2.53 (d, 1 H, J = 16.2 Hz), 2.83 (dd, 1 H, J = 5.4, 16.0 Hz), 3.67 (s, 3 H), 3.96 (s, 1 H), 4.18 (t, 1 H, J = 8.1 Hz), 4.66 (t, 1 H, J = 8.0 Hz), 4.82 (t, 1 H, J = 9.2 Hz), 5.06 (dd, 1 H, J = 5.2, 1.6 Hz), 6.28 (dd, 1 H, J = 6.0, 2.0 Hz), 7.15 (d, 1 H, J = 6.4 Hz), 7.28-7.46 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.5, 21.3, 45.4, 53.1, 64.4, 68.6, 70.6, 79.1, 89.3, 128.4, 129.5, 129.4, 140.2, 167.4, 171.4, 199.4 cm^-1. IR (thin film): 3280 (w), 2911 (w), 1766 (s) cm^-1. MS (APCI): m/e (%) = 344.1 (90) [M + H]⁺.
Compound 4b-D: R _f = 0.10 (50% EtOAc in hexane); [α]_D ²³ -132.6 (c 0.30, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 2.52 (d, 1 H, J = 16.8 Hz), 2.84 (dd, 1 H, J = 5.2, 16.4 Hz), 3.65 (s, 3 H), 3.96 (s, 0.35 H), 4.20 (dd, 1 H, J = 8.8, 6.8 Hz), 4.74 (t, 1 H, J = 8.4 Hz), 4.96 (t, 1 H, J = 7.6 Hz), 5.05 (m, 1 H) 6.28 (dd, 1 H, J = 1.6, 5.6 Hz), 7.11 (d, 1 H, J = 6.0 Hz), 7.23-7.44 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 29.5, 45.4, 53.0, 64.3, 70.5, 79.1, 89.2, 128.4, 129.5, 129.9, 132.6, 133.6, 136.4, 158.3, 167.3, 199.4. IR (thin film): 3300 (w), 2910 (w), 1748 (s) cm^-1. MS (APCI): m/e (%) = 345.1 (60) [M + H]⁺.
Compound 5b: R _f = 0.23 (50% EtOAc in hexane); [α]_D ²³
-72.8 (c 6.4, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 2.51 (d, 1 H, J = 16.0 Hz), 2.84 (dd, 1 H, J = 16.4, 6.0 Hz), 4.00 (s, 1 H), 4.17 (t, 1 H, J = 8.8 Hz), 4.39 (ddt, 1 H, J = 13.2, 5.6, 1.3 Hz), 4.66 (t, 1 H J = 8.4 Hz), 4.69 (m, 1 H), 4.83 (t, 1 H, J = 8.4 Hz), 5.07 (dd, 1 H, J = 5.6, 1.9 Hz), 5.27 (ddd, 1 H, J = 10.4, 2.5, 1.3 Hz) 5.34 (ddd, 1 H, J = 17.2, 3.0, 1.4 Hz) 5.84 (ddt, 1 H, J = 6.0, 11.6, 16.4), 6.28 (dd, 1 H, J = 6.0, 2.0 Hz), 6.72 (d, 1 H, 6.0 Hz), 7.28-7.41 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 45.4, 64.4, 66.7, 68.6, 70.6, 79.1, 89.3, 119.6, 128.5, 129.5, 129.9, 131.3, 132.8, 133.7, 136.5, 158.2, 166.8, 199.5. IR (thin film): 3629 (w), 3445 (w), 3065 (w), 1764 (s), 1726 (s) cm^-1. MS (APCI):
m/e (%) = 370.1 (100) [M + H]⁺.
Compound 9b: R _f = 0.13 (50% EtOAc in hexane); [α]_D ²³
-78.5 (c 2.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 2.52 (d, 1 H, J = 16.5 Hz), 2.79 (dd, 1 H, J = 17.0, 5.5 Hz), 3.84 (s, 1 H), 4.26 (dd, 1 H, J = 9.0, 7.0 Hz), 4.77 (t, 1 H, J = 8.5 Hz), 5.08 (d, 1 H, J = 4.0 Hz), 5.16 (t, 1 H, J = 8.0 Hz) 6.34 (br d, 1 H, J = 4.5 Hz), 6.37 (dd, 0.5 H, J = 6.0, 2.0 Hz), 6.61 (d, 0.5 H, J = 6.0 Hz), 7.41-7.48 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 29.6, 44.8, 45.3, 65.1, 71.4, 79.3, 79.7, 128.2, 128.8, 129.9, 130.2, 130.6, 132.8, 135.7, 197.2. IR (thin film): 3509 (w), 3110 (w), 2897 (w), 1755 (s), 1729 (s) cm^-1. MS (APCI): m/e (%) = 311.1 (10) [M + H]⁺.
Compounds 10a,b: R _f = 0.31 (50% EtOAc in hexane). ¹H NMR (400 MHz, CDCl₃): δ = 1.31 (s, 3 H), 1.43 (s, 3 H), 2.43 (d, 1 H, J = 16.5 Hz), 2.49 (d, 1 H, J = 15.5 Hz), 2.65 (d, 1 H, J = 15.5 Hz), 2.75-2.82 (br, 1 H), 4.08 (dd, 1 H, J = 8.0, 4.4 Hz), 4.19 (dd, 1 H, J = 8.4, 8.4 Hz), 4.74 (t, 2 H, J = 8.8 Hz), 4.82 (dd, 1 H, J = 9.2, 4.4 Hz), 4.87 (dd, 2 H, J = 8.4, 4.8 Hz), 4.92 (d, 2 H, J = 4.4 Hz), 4.99 (dd, 1 H, J = 5.6, 0.8 Hz), 5.92 (d, 1 H, J = 6.0 Hz), 6.06 (br, 1.8 H), 6.13 (dd, 0.50 H, J = 6.4, 2.0 Hz), 6.45 (d, 0.20 H, J = 5.6 Hz), 6.48 (dd, 0.50 H, J = 4.4, 1.0 Hz), 7.27-7.44 (m, 10 H). IR (thin film): 3425 (w), 2927 (m), 1751 (s), 1719 (s) cm^-1. MS (APCI): m/e (%) = 300.1 (100) [M + H]⁺.

22 Sibi MP. Porter NA. Acc. Chem. Res. 1999, 32: 163

23

When the reaction was carried out in the absence of ZnCl₂, it was very sluggish and inconclusive.