Synthetic Studies Towards Phorboxazole B: Stereoselective Synthesis of the C3-C19 Bis-oxane Oxazole Fragment

Abstract

A convergent and enantioselective synthesis of the C3-C19 bis-oxane oxazole fragment of phorboxazole B has been described. This work features highly efficient substrate-controlled reductions to construct the functionalised cis-oxane and a Mukaiyama aldol reaction followed by an intramolecular Williamson reaction leading to a trans-oxane.

Key words

enantioselective synthesis - phorboxazole - reduction - Mukaiyama reaction - Williamson reaction

References

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13

The configuration of 13 was confirmed by NOE measurements. Compound 13: ¹H NMR (600 MHz, CDCl₃) δ = 7.51 (s, 1 H), 7.14 (d, J = 8.7 Hz, 2 H), 6.75 (d, J = 8.7 Hz, 2 H), 4.73 (s, 2 H), 4.42 (s, 2 H), 4.36 (d, J = 10.5 Hz, 1 H), 3.85-3.90 (m, 1 H), 3.80 (s, 3 H), 3.64-3.67 (m, 1 H), 3.60-3.62 (m, 1 H), 3.53-3.56 (m, 1 H), 2.28 (dt, J = 12.6, 2.4 Hz, 1 H), 2.01 (dt, J = 12.3, 2.4 Hz, 1H), 1.88-1.93 (m, 1 H), 1.78-1.83 (m, 1 H), 1.34 (app q, J = 11.7 Hz, 1 H), 1.28 (app q, J = 10.5 Hz, 1 H), 0.92 (s, 9 H), 0.10 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 162.5, 159.1, 141.2, 135.2, 130.5 129.2, 113.7, 73.1, 72.5, 71.0, 67.8, 66.1, 58.3, 55.2, 40.9, 40.0, 36.0, 25.7, 18.3, -5.4.

15

The diastereoselective ratio was measured by HPLC analysis.

20

The relative stereochemistry between C5 and C9 of 4 was confirmed by NOE experiments. Compound 4: Colorless oil, [α]_D ²⁵ = -14.2 (c 0.35, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ = 7.65-7.68 (m, 4 H), 7.47 (s, 1 H), 7.37-7.40 (m, 6 H), 4.72 (d, J = 5.4 Hz, 2 H), 4.72 (s, 2 H), 4.27 (d, J = 10.8 Hz, 1 H), 4.02 (app q, J = 6.0 Hz, 1 H), 3.93 (app q, J = 6.0 Hz, 1 H), 3.67-3.83 (m, 3 H), 3.49-3.55 (m, 1 H), 2.36 (br s, 1 H), 2.35 (br s, 1 H), 2.12-2.16 (m, 1 H), 1.95-2.07 (m, 3 H), 1.88-1.92 (m, 1 H), 1.79-1.85 (m, 1 H), 1.62-1.70 (m, 1 H), 1.48-1.54 (m, 2 H), 1.20-1.33 (m, 1 H), 1.04 (s, 9 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.09 (s, 6 H), 0.034 (s, 3 H), 0.028 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ 162.4, 142.2, 141.8, 135.7, 135.2, 135.0, 134.0, 129.7, 127.8, 127.7, 110.4, 73.0, 71.4, 69.0, 68.7, 68.6, 60.7, 58.5, 41.2, 40.8, 40.0, 39.6, 39.6, 39.4, 36.5, 27.0, 26.7, 25.9, 19.3 (3 C), 18.5 (3 C), 18.1 (3 C), -4.4 (2 C), -5.3 (2 C). IR (cm^-1): 3073, 1655, 1093, 1112. HRMS (ESI) calcd for C₄₆H₇₃O₆NSi₃Na (M + Na)⁺: 842.4633, found: 842.4638.