Spliceostatins and Derivatives: Chemical Syntheses and Biological Properties of Potent Splicing Inhibitors

Abstract

Spliceostatins and thailanstatins are intriguing natural products due to their structural features as well as their biological significance. This family of natural products has been the subject of immense synthetic interest because they exhibit very potent cytotoxicity in representative human cancer cell lines. The cytotoxic properties of these natural products are related to their ability to inhibit spliceosomes. FR901564 and spliceostatins have been shown to inhibit spliceosomes by binding to their SF3B component. Structurally, these natural products contain two highly functionalized tetrahydropyran rings with multiple stereogenic centers joined by a diene moiety and an acyclic side chain linked with an amide bond. Total syntheses of this family of natural products led to the development of useful synthetic strategies, which enabled the synthesis of potent derivatives. The spliceosome modulating properties of spliceostatins and synthetic derivatives opened the door for understanding the underlying spliceosome mechanism as well as the development of new therapies based upon small-molecule splicing modulators. This review outlines the total synthesis of spliceostatins, synthetic studies of structural derivatives, and their bioactivity.

Figure 1.

Thailanstatin A SAR.

Scheme 1.

FR901464 Retrosynthesis

Scheme 2.

Synthesis of Vinyl Iodide 14

Scheme 3.

Synthesis of Vinyl Iodide 15

Scheme 4.

Synthesis of Carboxylic Acid 16

Scheme 5.

Jacobsen Synthesis of FR901464

Scheme 6.

FR901464 Retrosynthesis by Kitahara and Co-workers

Scheme 7.

Synthesis of Sulfone 49

Scheme 8.

Synthesis of Aldehyde 55

Scheme 9.

Synthesis of Carboxylic Acid 42

Scheme 10.

Kitahara Synthesis of FR901464

Scheme 11.

Synthetic Strategy for FR901464

Scheme 12.

Synthesis of Functionalized Tetrahydropyran 64

Scheme 13.

Synthesis of Tosyl Derivative 79

Scheme 14.

Koide Synthesis of 16

Scheme 15.

Koide Synthesis of FR901464

Scheme 16.

Synthesis of C-1-Dimethyl Analogue of FR901464

Scheme 17.

Synthesis of Meayamycin B (96)

Scheme 18.

Synthetic Strategy for FR901464 and Spliceostatin A

Scheme 19.

Synthesis of Tetrahydropyran Ring A 97

Scheme 20.

Synthesis of Z-Allylic Acetate 16

Scheme 21.

Synthesis of Tetrahydropyran Ring B 65

Scheme 22.

Synthesis of Spliceostatin A and FR901464

Scheme 23.

Synthetic Strategy for the C-1-Cyclopropane Derivative (122) of FR901464 (1)

Scheme 24.

Syntheses of Ring A Alkene 123 and Vinyl Iodide 124 Derivatives

Scheme 25.

Synthesis of Vinyl Boronate 125

Scheme 26.

Synthesis of C-1-Cyclopropane Derivative 122 via Cross-Metathesis

Scheme 27.

Synthesis of C-1-Cyclopropane Derivative 122 via Suzuki coupling

Scheme 28.

Synthesis of Spliceostatin G

Scheme 29.

Synthetic Strategy for Spliceostatin E

Scheme 30.

Synthesis of Dihydropyranone 142

Scheme 31.

Synthesis of Z-Allylic Acetate 16

Scheme 32.

Synthesis of Spliceostatin E

Scheme 33.

Synthetic Strategy for Thailanstatin A

Scheme 34.

Enantioselective Synthesis of 65 from Tri-O-acetyl-d-glucal

Scheme 35.

Synthesis of Epoxy Olefin Derivative 151

Scheme 36.

Final Coupling to Form Thailanstatin A Methyl Ester

Scheme 37.

Nicolaou’s Synthetic Strategy for Thailanstatin A

Scheme 38.

Synthesis of Vinyl Iodides 169 and 170

Scheme 39.

Nicolaou’s Synthesis of Z-Allylic Acetate 16

Scheme 40.

Synthesis of Dihydropyran Derivative 178

Scheme 41.

Optimized Synthesis of Vinyl Boronate 125

Scheme 42.

Syntheses of Spliceostatin D, Thailanstatin A, and Thailanstatin B

Scheme 43.

Synthesis of Thailanstatin C

Scheme 44.

Boger Meayamycin A (90) Retrosynthesis

Scheme 45.

Boger Synthesis of Tetrahydropyran Ring A

Scheme 46.

Boger Synthesis of Tetrahydropyran Ring B

Scheme 47.

Synthesis of O-Acyl Meayamycin Derivatives