Studies Towards the Synthesis of Superstolide A: An Aldol-Based Construction of an Advanced C1-C5/C20-C26 Segment

Abstract

Based on a boron-mediated syn aldol reaction of an alanine-derived ethyl ketone with an α-chiral aldehyde partner, an advanced intermediate for superstolide A was assembled in a highly stereocontrolled fashion. Controlled 1,3-anti reduction of the resulting β-hydroxy ketone gave the characteristic amino diol stereopentad of superstolide, followed by a Takai olefination and esterification of the C23 hydroxyl to provide the elaborated C1-C5/C20-C26 segment 3.

macrolide - boron aldol - α-amino ketones - esterification

References

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All new compounds gave spectroscopic data in agreement with the structures indicated. Compound 3: [α]_D ²⁰ +183.1 (c 0.16, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (1 H, dd, J = 15.3, 10.2 Hz, H₃), 6.34 (1 H, dd, J = 14.4, 8.8 Hz, H₂₁), 6.28 (1 H, d, J = 10.2 Hz, H₄), 6.15 (1 H, d, J = 14.4 Hz, H₂₀), 6.15 (1 H obs., NH), 5.97 (1 H, d, J = 15.3 Hz, H₂), 4.99 (1 H, dd, J = 9.7, 1.6 Hz, H₂₃), 4.18 (1 H, br qnd, J = 6.7, 2.0 Hz, H₂₆), 3.96 (1 H, d, J = 3.7 Hz, OH), 3.10 (1 H, m, H₂₅), 2.71 (3 H, s, Me₂₉), 2.61 (1 H, qd, m, H₂₂), 1.96 (3 H, s, NHCOMe), 1.77 (1 H, m, H₂₄), 1.07 (3 H, d, J = 6.7 Hz, Me₃₅), 1.03 (3 H, d, J = 6.9 Hz, Me₃₃), 0.88 (3 H, d, J = 7.0 Hz, Me₃₄). ¹³C NMR (100 MHz, CDCl₃): δ = 169.0, 168.5, 148.1, 147.6, 132.4, 121.6, 113.9, 77.7, 76.2, 73.0, 45.2, 42.5, 37.4, 35.0, 23.6, 16.1, 13.0, 8.4. HRMS (ES⁺): m/z calcd for [M + H]⁺ C₁₈H₂₈I₂NO₄: 576.0108; found: 576.0115. MS (ES⁺): m/z (%) = 576 (100) [M + H]⁺. Compound 19: [α]_D ²⁰ +13.0 (c 0.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (1 H, dd, J = 15.3, 10.3 Hz, H₃), 6.53 (1 H, dd, J = 14.4, 8.3 Hz, H₂₁), 6.30 (1 H, d, J = 9.9 Hz, H₄), 6.12 (1 H, d, J = 14.4 Hz, H₂₀), 6.06 (1 H, d, J = 15.3 Hz, H₂), 5.84 (1 H, br d, J = 8.0 Hz, NH), 4.98 (1 H, dd, J = 9.4, 2.2 Hz, H₂₅), 4.40 (1 H, br qn, J = 6.8 Hz, H₂₆), 3.27 (1H, dd, J = 9.2, 2.2 Hz, H₂₃), 2.72 (3 H, s, Me₂₉), 2.53 (1 H, d, J = 4.0 Hz, OH), 2.43 (1 H, m, H₂₂), 1.95 (3 H, s, NHCOMe), 1.84 (1 H, m, H₂₄), 1.15 (3 H, d, J = 6.7 Hz, Me₃₅), 0.96 (3 H, d, J = 7.0 Hz, Me₃₃), 0.94 (3 H, d, J = 6.9 Hz, Me₃₄). ¹³C NMR (100 MHz, CDCl₃): δ = 169.3, 167.7, 149.5, 147.9, 132.3, 121.8, 114.1, 78.8, 75.8, 72.4, 45.8, 43.9, 36.6, 35.0, 23.5, 15.8, 14.1, 8.2. HRMS (ES⁺): m/z calcd for [M + H]⁺ C₁₈H₂₈I₂NO₄: 576.0108; found: 576.0104. MS (CI⁺): m/z (%) = 576 (1) [M + H]⁺, 98 (100).

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