Calyculins and related marine natural products as serine-threonine protein phosphatase PP1 and PP2A inhibitors and total syntheses of calyculin A, B, and C

Abstract

Calyculins, highly cytotoxic polyketides, originally isolated from the marine sponge Discodermia calyx by Fusetani and co-workers, belong to the lithistid sponges group. These molecules have become interesting targets for cell biologists and synthetic organic chemists. The serine/threonine protein phosphatases play an essential role in the cellular signalling, metabolism, and cell cycle control. Calyculins express potent protein phosphatase 1 and 2A inhibitory activity, and have therefore become valuable tools for cellular biologists studying intracellular processes and their control by reversible phosphorylation. Calyculins might also play an important role in the development of several diseases such as cancer, neurodegenerative diseases, and type 2-diabetes mellitus. The fascinating structures of calyculins have inspired various groups of synthetic organic chemists to develop total syntheses of the most abundant calyculins A and C. However, with fifteen chiral centres, a cyano-capped tetraene unit, a phosphate-bearing spiroketal, an anti, anti, anti dipropionate segment, an alpha-chiral oxazole, and a trihydroxylated gamma-amino acid, calyculins reach versatility that only few natural products can surpass, and truly challenge modern chemists' asymmetric synthesis skills.

Keywords: marine natural products; protein phosphatase inhibitors; total synthesis.

Figure 1

Calyculins and calyculinamides.

Figure 2

PP2A-selective inhibitors.

Figure 3

Right: microcystin-LR (18); left: motuporin (19).

Figure 4

Tautomycin 20.

Figure 5

Calyculin related structures.

Figure 6

Binding models of calyculin A to PP1.

Scheme 1

Retrosynthetic analysis of the calyculin skeleton (X, Y and Z denote the functional groups suitable for coupling).

Scheme 2

Retrosynthetic analysis of the C₂₆–C₃₇ fragment (X denotes the functional group suitable for coupling with the fragment C₉–C₂₅).

Scheme 3

Retrosynthetic analysis of C₁–C₉ fragment (X denotes the functional groups suitable for coupling).

Scheme 4

Preparation of phosphonate 32.

Scheme 5

Preparation of stannane 33 by Masamune.

Scheme 6

Preparation of phosphonate 34.

Scheme 7

Preparation of stannane 33 by Shioiri.

Scheme 8

Preparation of tetraene 54.

Scheme 9

Preparation of phosphonate 30.

Scheme 10

Preparation of phosphonate 32.

Scheme 11

Preparation of stannane 33 by Barrett.

Scheme 12

Synthesis of vinyl iodide 67.

Scheme 13

Preparation of 32 by Koskinen.

Scheme 14

Retrosynthetic analysis of C₉-C₂₅ fragment. (Y denotes the functional groups suitable for coupling and P protective groups).

Scheme 15

Preparation of ketone 76.

Scheme 16

Formation of spiroketal 79.

Scheme 17

Preparation of 85.

Scheme 18

Preparation of 95.

Scheme 19

Preparation of spiroketal 99.

Scheme 20

Preparation of ketone 105.

Scheme 21

Synthesis of spiroketal 112.

Scheme 22

Synthesis of epoxides 116.

Scheme 23

Preparation of spiroketal 122.

Scheme 24

Preparation of fragment 127.

Scheme 25

Preparation of spiroketal 134.

Scheme 26

Preparation of 139.

Scheme 27

Preparation of aldehyde 143.

Scheme 28

Preparation of spiroketal 150.

Scheme 29

Preparation of 157.

Scheme 30

Preparation of spiroketal 161.

Scheme 31

Retrosynthetic analysis of C₂₆–C₃₂ fragment (X denotes the functional groups suitable for coupling and P the protective group).

Scheme 32

Preparation of oxazole 167.

Scheme 33

Preparation of oxazole 172.

Scheme 34

Preparation of oxazole 179.

Scheme 35

Preparation of oxazole 184.

Scheme 36

Preparation of oxazole 190.

Scheme 37

Preparation of oxazole 196.

Scheme 38

Preparation of oxazole 200.

Scheme 39

Retrosynthetic analysis of C₃₃–C₃₇ fragment.

Scheme 40

Preparation of 205.

Scheme 41

Preparation of 209.

Scheme 42

Preparation of ester 213.

Scheme 43

Preparation of 218.

Scheme 44

Preparation of 222.

Scheme 45

Preparation of 227.

Scheme 46

Preparation of 232.

Scheme 47

Preparation of the C₂₆–C₃₇ fragment 235.

Scheme 48

Final steps for the synthesis of ent-calyculin A.

Scheme 49

Preparation of C₂₆–C₃₇ fragment 240.

Scheme 50

Final steps to calyculin A.

Scheme 51

Preparation of C₂₆–C₃₇ 235 by Shioiri.

Scheme 52

Preparation of 243.

Scheme 53

Preparation of C₂₆–C₃₇ fragment 249.

Scheme 54

Final steps to ent-calyculin A and B.

Scheme 55

Preparation of C₂₆–C₃₇ fragment 254.

Scheme 56

Final steps to calyculin C.

Scheme 57

Preparation of the C₂₆–C₃₇ fragment 234 by Barrett.

Scheme 58

Preparation of the C₁–C₂₅ fragment 236 by Barrett.