Synthesis of the Skipped Polyene Chain and Its Neighboring Highly ­Oxygenated Pyran Ring en route to Delivering the C(43)-C(67) Subsector of Amphidinol 3

Abstract

An approach toward a total synthesis of amphidinol 3 that focuses on elaboration of the C(43)-C(67) subunit is described. The Julia-Kocienski reaction constitutes a straightforward way to unite the skipped polyolefin chain to the adjacent highly functionalized pyran ring.

Key words

polyketide metabolite - carbohydrate homologation - ­selective desilylation - Julia-Lythgoe reaction - Julia-Kocienski ­reaction

References

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  The value of the tert-butyl group in minimizing intramolecular cyclization is noted.

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18

Compound 16: IR (neat): 1727, 1650 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 9.76 (t, J = 1.6 Hz, 1 H), 6.30 (dt, J = 16.9, 10.2 Hz, 1 H), 6.19-6.00 (m, 5 H), 5.72-5.58 (m, 3 H), 5.09 (dd, J = 16.9, 1.5 Hz, 1 H), 4.96 (d, J = 10.1 Hz, 1 H), 2.60-2.50 (m, 2 H), 2.50-2.32 (m, 2 H), 2.22-2.14 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 201.8, 137.2, 134.3, 134.0, 131.8, 131.7, 131.4, 131.3, 130.8, 130.4, 115.1, 43.3, 32.4, 32.3, 25.3.

21

The ensuing transformations exemplify the problem as manifested in rather different contexts (Scheme [5] ).

28

Compound 28: IR (neat): 3456, 1657, 1589 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.70-7.63 (m, 4 H), 7.44-7.33 (m, 6 H), 5.79-5.73 (m, 1 H), 5.64-5.55 (m, 2 H), 5.27 (ddd, J = 15.8, 5.2, 5.2 Hz, 1 H), 4.46 (s, 2 H), 4.26 (t, J = 2.9 Hz, 1 H), 4.18-4.11 (m, 3 H), 4.07-4.04 (m, 1 H), 3.80 (dd, J = 5.5, 1.2 Hz, 2 H), 3.57-3.51 (m, 2 H), 2.35-2.29 (m, 2 H), 1.77 (br, 1 H), 1.39 (s, 3 H), 1.30 (s, 3 H), 1.03 (s, 9 H), 0.90 (t, J = 8.3 Hz, 2 H), 0.02 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 136.0, 135.9, 133.8, 133.7, 131.5, 130.8, 130.5, 129.7, 129.6, 129.3, 127.5, 127.4, 108.3, 93.7, 80.0, 76.8, 73.2, 66.6, 65.0, 57.9, 28.6, 27.6, 27.0, 25.4, 19.2, 18.0,
-1.38. HRMS (ES): m/z calcd 649.3351[(M + Na]⁺; found: 649.3347. [α]_D ²⁰ +23.0 (c 1.22, CHCl₃).

35

Compound 36: IR (neat): 1599, 1490 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.47-7.43 (m, 6 H), 7.29-7.26 (m, 6 H), 7.26-7.21 (m, 3 H), 6.30 (dt, J = 17.0, 10.3 Hz, 1 H), 6.20-5.97 (m, 5 H), 5.80 (dt, J = 15.2, 4.9 Hz, 1 H), 5.72-5.62 (m, 3 H), 5.44 (dd, J = 15.4, 7.8 Hz, 1 H), 5.10 (d, J = 16.9 Hz, 1 H), 4.97 (d, J = 10.1 Hz, 1 H), 4.75 (d, J = 6.8 Hz, 1 H), 4.69 (d, J = 6.7 Hz, 1 H), 4.39-4.27 (m, 2 H), 4.24 (dd, J = 6.0, 6.0 Hz, 1 H), 4.08-4.02 (m, 1 H), 3.87-3.81 (m, 2 H), 3.71 (ddd, J = 7.9, 4.9, 4.9 Hz, 1 H), 3.35-3.32 (m, 1 H), 3.34 (s, 3 H), 3.20 (dd, J = 10.0, 5.4 Hz, 1 H), 2.22-2.10 (m, 8 H), 1.89-1.84 (m, 1 H), 1.75-1.68 (m, 1 H), 1.44 (s, 3 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.33 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 143.9, 137.1, 136.2, 134.3, 133.5, 133.0, 131.3, 131.2, 131.0, 130.9, 128.7, 127.8, 127.0, 126.9, 115.1, 109.2, 108.7, 98.7, 96.8, 86.7, 82.1, 78.2, 77.7, 72.1, 71.5, 70.8, 63.3, 55.9, 32.4, 32.3, 32.2, 29.7, 29.0, 27.9, 27.2, 26.8, 25.6. HRMS (ES): m/z calcd 839.4493 [M + Na]⁺; found: 839.4479. [α]_D ²⁰ -6.8 (c 0.40, C₆H₆).