A One-Pot Deprotection and Intramolecular Oxa-Michael Addition to Access Angular Trioxatriquinanes

Abstract

An efficient one-pot deprotection-oxa-Michael addition strategy has been used to synthesize a few trioxatriquinanes starting from commercially available sugars.

triquinane - RCM - allylic oxidation - deprotection

References and Notes

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<A NAME="RD22311ST-18">18</A>

A 60% oil dispersion of NaH (75 mg, 1.84 mmol, 3 equiv), after washing with anhyd hexanes (3 × 5 mL), was suspended in anhyd THF (5 mL), and the reaction mixture was cooled to 0 ˚C. To this, a solution of compound 16 (280 mg, 0.61 mmol, 1 equiv) in anhyd THF (5 mL) was added dropwise and allowed to stir at r.t. for 1 h. Allyl bromide (0.1 mL, 1.23 mmol, 2 equiv) and TBAI (cat.) were added to the mixture at 0 ˚C, which was further stirred for 1 h at r.t. followed by heating to reflux for 4 h. The mixture was quenched by the careful addition of sat. aq NH₄Cl and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give the crude product. Silica gel column chromatography of the residue, eluting with 4% EtOAc in hexanes provided 22 (230 mg, 76%) as a colorless syrup. R _f  = 0.45 (10% EtOAc in hexanes); [α]_D ^²0 28.9 (c 1.14, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.70-7.67 (m, 4 H), 7.42-7.33 (m, 6 H), 5.94-5.85 (m, 1 H), 5.81 (d, J = 3.6 Hz, 1 H), 5.58 (dd, J = 17.8, 11.3 Hz, 1 H), 5.25 (dd, J = 11.3, 0.9 Hz, 1 H), 5.23 (dq, J = 17.2, 1.8 Hz, 1 H), 5.16 (dd, J = 17.8, 0.9 Hz, 1 H), 5.11 (dq, J = 10.4, 1.5 Hz, 1 H), 4.45 (d, J = 3.6 Hz, 1 H), 4.33 (dd, J = 7.1, 3.5 Hz, 1 H), 4.10 (ddt, J = 12.4, 5.1, 1.6 Hz, 1 H), 3.98 (ddt, J = 12.4, 5.3, 1.6 Hz, 1 H), 3.78 (dd, J = 11.4, 3.5 Hz, 1 H), 3.70 (dd, J = 11.4, 7.2 Hz, 1 H), 1.61 (s, 3 H), 1.36 (s, 3 H), 1.03 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 135.9, 135.8, 135.1, 134.6, 133.8, 133.7, 129.7, 129.6, 127.8, 127.7, 117.9, 116.0, 112.9, 104.5, 84.9, 82.8, 81.8, 66.3, 63.5, 27.2, 27.0, 26.9, 19.4. IR (neat): ν = 3072, 2932, 2858, 1646, 1462, 1428, 1383, 1217, 1121, 1042, 927, 878, 823, 758, 704, 612, 548, 505 cm^-¹. ESI-HRMS: m/z calcd for C₂₉H₃₈O₅SiNa [M + Na]⁺: 517.2386; found: 517.2380.

<A NAME="RD22311ST-19">19</A>

To a solution of diene 22 (210 mg, 0.42 mmol, 1 equiv) in argon-purged CH₂Cl₂ was added Grubbs first-generation catalyst (5 mol%), and the mixture was refluxed for 12 h. DMSO (2-3 drops) was added and the mixture stirred for
6 h to remove metal impurities. The mixture was then concentrated in vacuo to give a residue which, upon purification by silica gel column chromatography with 14% EtOAc in hexane, afforded compound 23 (180 mg, 91%) as a colorless syrup. R _f  = 0.26 (16% EtOAc in hexanes); [α]_D ^²0 +27.6 (c 1.56, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.69-7.65 (m, 4 H), 7.43-7.34 (m, 6 H), 5.98 (dt, J = 6.2, 1.3 Hz, 1 H), 5.80 (d, J = 3.6 Hz, 1 H), 5.67 (dt, J = 6.2, 1.5 Hz, 1 H), 4.69 (ddd, J = 13.4, 2.5, 1.7 Hz, 1 H) 4.57 (ddd, J = 13.4, 2.4, 1.7 Hz, 1 H), 4.32 (t, J = 4.5 Hz, 1 H), 4.22 (d, J = 3.7 Hz, 1 H), 3.68, 3.64 (ABq, J _AB = 11.4 Hz, 1 H), 3.66, 3.63 (ABq, J _AB = 11.4 Hz, 1 H), 1.63 (s, 3 H), 1.36 (s, 3 H), 1.03 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 135.9, 135.8, 133.6, 133.5, 129.8, 129.6, 127.8, 125.6, 113.2, 103.5, 95.8, 83.0, 80.4, 75.9, 63.0, 27.0, 26.9, 26.6, 19.3. IR (neat): ν = 3019, 2930, 2857, 1597, 1216, 1113, 1082, 1042, 758, 668 cm^-¹. ESI-HRMS: m/z calcd for C₂₇H₃₄O₅SiNa [M + Na]⁺: 489.2073; found: 489.2081.

<A NAME="RD22311ST-20">20</A> Chidambaram N. Chandrasekaran S. J. Org. Chem.  1987,  52:  5048 

<A NAME="RD22311ST-21">21</A>

To a solution of spiroether 23 (260 mg, 0.56 mmol, 1 equiv) in benzene (20 mL) was added Celite (1.2 g/mmol) at r.t. and the mixture cooled to 0-10 ˚C. To this reaction mixture was added PDC (1.06 g, 2.8 mmol, 5 equiv), followed by t-BuOOH (0.39 mL, 2.8 mmol, 5 equiv), and the whole was stirred for 8 h at r.t. The reaction mixture was filtered through a pad of Celite and washed with EtOAc, the filtrate was concentrated in vacuo to furnish the crude product as a yellow syrup. Silica gel column chromatography, eluting with 20% EtOAc in hexanes afforded the spirolactone 21 (230 mg) as a colorless syrup in 85% yield. R _f  = 0.39 (40% EtOAc in hexanes); [α]_D ^²0 +52.2 (c 1.41, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.66-7.59 (m, 4 H), 7.53 (d, J = 5.7 Hz, 1 H), 7.46-7.36 (m, 6 H), 6.14 (d, J = 5.7 Hz, 1 H), 5.98 (d, J = 3.7 Hz, 1 H), 4.52 (t, J = 3.7 Hz, 1 H), 4.49 (d, J = 3.7 Hz, 1 H), 3.73 (dd, J = 11.9, 4.1 Hz, 1 H), 3.61 (dd, J = 11.9, 3.6 Hz, 1 H), 1.63 (s, 3 H), 1.36 (s, 3 H), 1.03 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 170.9, 153.8, 135.7, 135.6, 132.7, 132.6, 130.1, 130.0, 128.0, 127.9, 121.3, 114.3, 103.5, 91.4, 81.6, 79.2, 61.0, 26.9, 26.8, 26.7, 19.3. IR (neat): ν = 3021, 2933, 2860, 1774, 1601, 1216, 1166, 1106, 1013, 759, 670 cm^-¹. ESI-HRMS: m/z calcd for C₂₇H₃₂O₆SiNa [M + Na]⁺: 503.1866; found: 503.1879.

<A NAME="RD22311ST-22">22</A>

To a solution of spirolactone 21 (270 mg, 0.56 mmol, 1 equiv) in anhyd THF (6 mL) was added TBAF solution in THF (1 M, 1.12 mL, 2 equiv) at 0 ˚C, and the mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with EtOAc, and solvents were removed in vacuo to obtain the crude product, which was purified by silica gel chromatography, eluting with 32% EtOAc in hexanes to afford the trioxatriquinane 12 (80 mg) as a white low-melting solid in 60% yield. R _f  = 0.19 (40% EtOAc in hexanes); [α]_D ^²0 +27.8 (c 1.29, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 5.99 (d, J = 3.6 Hz, 1 H), 4.82 (d, J = 2.9 Hz, 1 H), 4.59 (d, J = 3.6 Hz, 1 H), 4.55 (dd, J = 6.7, 1.3 Hz, 1 H), 4.13 (d, J = 11.0 Hz, 1 H), 4.03 (dd, J = 11.0, 2.9 Hz, 1 H), 2.88 (dd, J = 19.0, 6.7 Hz, 1 H), 2.74 (dd, J = 19.0, 1.3 Hz, 1 H), 1.63 (s, 3 H), 1.39 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.6, 114.6, 105.9, 97.7, 83.0, 79.6, 79.2, 72.3, 35.5, 27.2, 27.0. IR (neat): ν = 3021, 2937, 1799, 1731, 1376, 1217, 1106, 1012, 909, 870, 758, 712, 669 cm^-¹. ESI-HRMS: m/z calcd for C₁₁H₁₄O₆Na [M + Na]⁺: 265.0688; found: 265.0682.

<A NAME="RD22311ST-23">23</A> Mukai C. Moharram SM. Azukizawa S. Hanaoka M. J. Org. Chem.  1997,  62:  8095 

<A NAME="RD22311ST-24">24</A> Nielsen P. Petersen M. Jacobsen JP. J. Chem. Soc., Perkin Trans. 1  2000,  3706