Total Synthesis of (+)-Cephalosporolide E and (-)-Cephalosporolide F en route to Bassianolone

Abstract

A stereoselective synthesis of (+)-cephalosporolide E and (-)-cephalosporolide F en route to bassianolone is described. The key steps involve cross metathesis to get the desired β,γ-unsaturated ester, asymmetric dihydroxylation to install the β-hydroxy-γ-lactone moiety and spiroketalization. Although attempts to get free bassianolone failed, the first total synthesis of natural cephalosporolides E and F has been achieved in nine steps and 6.3% and 3.5% overall yields, respectively.

Key words

bassianolone - cephalosporolides - cross metathesis - asymmetric dihydroxylation - spiroketalization

References and Notes

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9

^¹H NMR and ^¹³C NMR studies of purified product indicated single diastereomer.
Data for 18
Colourless oil; [α]_D ^²5 +10.2 (c 0.2, CHCl₃). IR (CHCl₃): ν = 3463, 3022, 2973, 1772, 1646, 1528, 1421, 1347, 1216, 1045, 927, 669 cm^-¹. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 0.02 (s, 3 H), 0.03 (s, 3 H), 0.86 (s, 9 H), 1.11 (d, J = 6.1 Hz, 3 H), 1.43-1.49 (m, 2 H), 1.50-1.58 (m, 1 H), 1.72-1.80 (m, 1 H), 2.24-2.37 (m, 2 H), 2.54 (d, J = 17.7 Hz, 1 H), 2.72 (dd, J = 17.7, 5.8 Hz, 1 H), 3.44 (br s, OH), 3.75-3.80 (m, 1 H), 3.93-4.02 (m, 4 H), 4.36-4.38 (m, 1 H), 4.55-4.60 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = -4.83, -4.39, 18.0, 23.6, 25.7 (3 C), 32.7, 33.7, 34.1, 37.7, 64.1, 64.5, 67.9, 68.3, 80.9, 110.1, 175.3. HRMS (ESI-TOF): m/z calcd for C₁₈H₃₄O₆Si + Na: 397.2022; found: 397.2028.

10

Data for 19
Colourless oil; [α]_D ^²5 -20.4 (c 0.1, CHCl₃). IR (CHCl₃): ν = 3440, 3018, 2965, 2931, 1773, 1636, 1458, 1407, 1378, 1216, 1160, 1062, 949, 668 cm^-¹. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 1.21 (d, J = 6.4 Hz, 3 H), 1.47-1.57 (m, 2 H), 1.79-1.87 (m, 2 H), 2.33-2.36 (m, 2 H), 2.56 (d, J = 17.7 Hz, 1 H), 2.76 (dd, J = 17.8, 5.9 Hz, 1 H), 3.36-3.45 (br s, OH), 3.78-3.82 (m, 1 H), 3.98-4.06 (m, 4 H), 4.39-4.41 (m, 1 H), 4.56-4.61 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 23.6, 33.3 (2 C), 34.3, 37.9, 64.3, 64.7, 67.6, 68.5, 81.1, 110.1, 175.5. HRMS (ESI-TOF): m/z calcd for C₁₂H₂₀O₆ + H: 261.1338; found: 261.1341.