Synthesis of the C₁-C₂₁ Southern Hemisphere of the Originally Proposed Structure of Spirastrellolide A

Abstract

A stereocontrolled synthesis of the C₁-C₂₁ [6,6]-spiro­acetal-containing domain of the originally assigned structure of spirastrellolide­ A is reported, exploiting asymmetric boron aldol methodology and an alkyne addition to a C₁₇ aldehyde. Comparison of the ¹H NMR data obtained for this synthetic fragment with that for the corresponding region of spirastrellolide suggested some stereochemical reassignment was required.

total synthesis - spiro compounds - macrolides - aldol reaction­s - asymmetric synthesis

References

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5

In addition to the originally proposed structure by Professor Andersen, as reported in ref. 1, a preliminary stereochemical assignment was made by us for the C₁-C₁₁ region.

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11

All new compounds gave spectroscopic data in agreement with the assigned structures. Compound 2 had [α]_D ²² = +34.5 (c 0.80, CHCl₃); ¹H NMR (500 MHz, C₆D₆): δ = 7.78-7.83 (m, 4 H, ArH), 7.22-7.29 (m, 6 H, ArH), 5.60 (dd, J = 9.9, 2.4 Hz, 1 H, H₁₅), 5.51 (dd, J = 9.9, 1.7 Hz, 1 H, H₁₆), 4.38 (m, 1 H, H₁₁), 4.22 (m, 1 H, H₉), 4.07 (m, 1 H, H₃), 4.03 (m, 1 H, H₇), 3.94 (m, 1 H, H_21eq.), 3.88 (m, 3 H, 2 × H₁, H_21ax.), 3.81 (m, 1 H, H₁₃), 3.15 (m, 1 H, H₂₀), 3.10 (s, 3 H, OMe), 2.12 (m, 1 H, H₈), 2.10 (m, 1 H, H₂), 2.09 (1H, m, H₁₀), 2.04 (m, 1 H, H₁₀), 2.02 (m, 1 H, H₁₄), 1.97 (m, 1 H, H_19ax.), 1.93 (m, 2 H, 2 × H₁₂), 1.84 (m, 1 H, H_18eq., H_19eq.), 1.82 (m, 1 H, H₂), 1.76 (m, 1 H, H₈), 1.65 (m, 1 H, H_6eq.), 1.58 (m, 1 H, H_4eq.), 1.50 (m, 1 H, H_18ax.), 1.49 (m, 2 H, 2 × H₅), 1.36 (m, 1 H, H_6ax.), 1.25 (m, 1 H, H_4ax.), 1.19 (s, 9 H, Si ^t Bu), 1.05 (s, 9 H, Si ^t Bu), 1.03 (s, 9 H, Si ^t Bu), 0.80 (d, J = 7.1 Hz, 3 H, Me₁₄), 0.26 (s, 3 H, SiMe), 0.28 (s, 3 H, SiMe), 0.24 (s, 3 H, SiMe), 0.20 (s, 3 H, SiMe); ¹³C NMR (125 MHz, C₆D₆): δ = 135.8, 135.7, 134.2, 134.1, 134.0, 129.7, 129.4, 93.0, 74.9, 71.0, 68.4, 68.3, 67.7, 67.6, 63.7, 61.5, 55.7, 46.6, 43.0, 42.5, 36.3, 34.5, 34.3, 30.8, 29.8, 27.0, 26.1, 26.0, 25.3, 19.3, 18.8, 18.2, 18.1, 17.0, -3.5, -3.7, -3.9, -4.0; HRMS (ES+): m/z [M + H]⁺ calcd for C₅₁H₈₇O₇Si₃: 895.5754; found: 895.5752.

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15b

Dihydropyranone 12 was conveniently accessed via a Jacobsen hetero-Diels-Alder reaction between Danishefsky’s diene and TPSO(CH₂)₂CHO in 94% yield and 99% ee.

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