Azaviridins as New Scaffolds for the Development of PI-3K Inhibitors

Abstract

We have designed a new class of non-natural furanosteroids to serve as more chemically stable analogues of the viridins, potent inhibitors of PI-3K. Central to the design is the incorporation of a nitrogen atom into the steroidal ring system to attenuate the activity of the electrophilic 2,4-diacylfuran common to these natural products. In this manuscript, we describe our initial synthetic studies on this ring system and the preparation of key intermediates for analogue generation.

natural products - heterocycles - furans - amination - palladium

References and Notes

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12

Selected Characterization Data for Compound 18
^¹H NMR (500 MHz, CD₃OD): δ = 9.10 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 8.25 (s, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H). ^¹³C NMR (125 MHz, CD₃OD): δ = 167.5, 152.6, 150.4, 133.2, 129.8, 129.7, 125.9, 125.3, 119.9, 119.5, 103.4, 79.6, 62.6, 14.8. IR (KBr): 3087, 2964, 1633, 1598, 1573 cm^-¹. HRMS-FAB: m/z calcd for C₁₄H₁₁BrNO₆ [M + H]⁺: 335.9866; found: 335.9866.

13

Selected Characterization Data for Compound 20
^¹H NMR (500 MHz, CDCl₃): δ = 9.26 (d, J = 1.9 Hz, 1 H), 8.29 (dd, J = 2.0 Hz, 1 H), 7.52 (s, 1 H), 7.35 (d, J = 8.9 Hz, 1 H), 6.63 (dt, J = 2.2, 10.1 Hz, 1 H), 6.00 (dt, J = 3.3, 10.1 Hz, 1 H), 4.99 (s, 2 H), 4.42 (q, J = 7.1 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 166.2, 164.7, 142.0, 141.8, 137.1,136.5, 132.4,130.2, 127.2, 124.5, 123.1, 115.9, 113.6, 111.9, 61.4, 46.6, 14.7. ESI-HRMS: m/z calcd for C₁₇H₁₄NO₄ [M + H]⁺: 296.0923; found: 296.0917.