Total Synthesis and Stereochemical Revision of Burkholdac A

Abstract

A stereocontrolled total synthesis of burkholdac A was completed, leading to a revision of the reported stereochemistry.

Key words

burkholdac A - total synthesis - antitumor - stereochemical assignment

References and Notes

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13

Synthesis of the Proposed Burkholdac A (1)
Compound 2 (46 mg, 0.04 mmol) was dissolved in MeOH-CH₂Cl₂ (50 mL, 1:9) and added to a vigorously stirred solution of I₂ (126 mg, 0.50 mmol) in MeOH-CH₂Cl₂ (200 mL, 1:9) at r.t. over 0.5 h. After 10 min, the reaction was quenched by addition of sat. aq solution of Na₂S₂O₃ (20 mL) and concentrated in vacuo. The residue was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with sat. aq solution of Na₂S₂O₃ (20 mL) and brine (30 mL), dried over anhyd Na₂SO₄ and concentrated in vacuo. The residue was dissolved in pyridine (1 mL), after HF˙py (0.8 mL) was added at 0 ˚C, the reaction mixture was stirred at r.t. for 12 h. All volatiles were removed in vacuo; the residue was diluted with EtOAc (100 mL) and washed with HCl (20 mL, 1.0 M in H₂O) and brine (20 mL), dried over anhyd Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography (eluted with EtOAc-hexanes-MeOH = 3:1:0.3) to provide the desired compound 1 (13.4 mg, 63% yield over 2 steps) as a white amorphous solid: [α]_D ^²0 -166.5 (c 0.35, MeOH). ^¹H NMR (400 MHz, CD₃CN): δ = 7.71 (d, J = 5.4 Hz, 1 H), 7.09 (d, J = 9.8 Hz, 1 H), 7.02 (br s, 1 H), 5.90 (br s, 1 H), 5.77 (d, J = 15.5 Hz, 1 H), 5.58 (dd, J = 6.1, 2.3 Hz, 1 H), 4.74 (br s, 1 H), 3.97-3.92 (m, 1 H), 3.83 (ddd, J = 10.2, 6.5, 4.0 Hz, 1 H), 3.68 (td, J = 10.3, 3.0 Hz, 1 H), 3.40-3.22 (m, 2 H), 2.73-2.67 (m, 2 H), 2.64-2.56 (m, 3 H), 2.51-2.43 (m, 3 H), 2.40-2.26 (m, 3 H), 2.18-2.08 (m, 2 H), 2.06 (s, 3 H), 0.83 (d, J = 0.8 Hz, 3 H), 0.81 (d, J = 1.0 Hz, 3 H) ppm. ^¹³C NMR (100 MHz, CD₃CN): δ = 172.4, 171.4, 171.2, 170.8, 131.9, 131.0, 70.0, 69.6, 60.1, 54.9, 54.8, 43.7, 41.2, 41.2, 41.1, 31.4, 29.1, 28.3, 20.8, 15.6, 15.0 ppm. ESI-HRMS m/z calcd for C₂₂H₃₆N₃O₆S₃ ⁺ [M + H]⁺: 534.1761; found: 534.1757.

14

The Analytical Data of the Revised Burkholdac A ( epi- 1)
[α]_D ^²0 -54.0 (c 0.23, MeOH). ^¹H NMR (500 MHz, CD₃CN): δ = 7.51 (s, 1 H), 7.41 (d, J = 6.9 Hz, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 6.12-6.06 (m, 1 H), 5.90 (d, J = 15.5 Hz, 1 H), 5.56-5.54 (m, 1 H), 4.70 (td, J = 9.2, 3.6 Hz, 1 H), 4.47-4.43 (m, 1 H), 4.18-4.13 (m, 1 H), 3.33-3.30 (m, 1 H), 3.21 (d, J = 10.5 Hz, 1 H), 3.13 (d, J = 14.0 Hz, 1 H), 2.96 (dd, J = 13.1, 7.2 Hz, 1 H), 2.86-2.57 (m, 8 H), 2.25 (dq, J = 13.6, 6.8 Hz, 1 H), 2.10 (s, 3 H), 2.08-2.01 (m, 2 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. ^¹³C NMR (125 MHz, CD₃CN): δ = 173.0, 172.2, 171.7, 170.1, 132.4, 131.5, 71.7, 69.0, 63.2, 56.8, 56.4, 41.8, 41.1, 40.8, 33.3, 31.2, 30.6, 30.5, 21.1, 19.8, 15.2 ppm. ESI-HRMS: m/z calcd for C₂₂H₃₆N₃O₆S₃ ⁺ [M + H]⁺: 534.1761; found: 534.1760.