Total Syntheses of Pladienolide-Derived Spliceosome Modulators

Abstract

Pladienolides, an emerging class of naturally occurring spliceosome modulators, exhibit interesting structural features, such as highly substituted 12-membered macrocycles and epoxide-containing diene side chains. The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product.

Keywords: macrocycles; natural products; pladienolide class; spliceosome; total synthesis.

Figure 1

Representative examples of naturally occurring spliceosome modulators.

Figure 2

Chemical structure of pladienolides A–G (1–7), 6-deoxypladienolide D (8), FD-895 (9), and synthetic analogs (10 and 11). The colors show the part of each compound that is structurally different from the structure of pladienolide A (1).

Figure 3

Brief summary of the disconnections of pladienolides as reported, 2007–2021.

Scheme 1

Kotake’s retrosynthetic analysis of pladienolides A and B (2007).

Scheme 2

Preparation of three fragments for the synthesis of pladienolide B (Kotake, 2007).

Scheme 3

Completion of the total synthesis of pladienolides A and B (Kotake, 2007).

Scheme 4

Preparation of the side chain fragment and completion of the total synthesis of pladienolide D (Kotake, 2007).

Scheme 5

Ghosh and Anderson’s retrosynthetic analysis of pladienolide B (2012).

Scheme 6

Preparation of the fragments for the synthesis of pladienolide B (Ghosh and Anderson, 2012).

Scheme 7

Final stage of the total synthesis of pladienolide B (2) (Ghosh and Anderson, 2012).

Scheme 8

Burkart’s retrosynthetic analysis of FD-895 (2012).

Scheme 9

Synthesis of macrocyclic core 64 (Burkart, 2012).

Scheme 10

Final stage of the total synthesis of FD-895 (Burkart, 2012).

Scheme 11

Kumar and Chandrasekhar’s retrosynthetic analysis of pladienolide B (2013).

Scheme 12

Construction of the macrocyclic core unit 82 (Kumar and Chandrasekhar, 2013).

Scheme 13

Final stage of the total synthesis of pladienolide B (Kumar and Chandrasekhar, 2013).

Scheme 14

Synthesis of truncated pladienolide B analogs (Kumar and Chandrasekhar, 2013).

Scheme 15

Keaney’s retrosynthetic analysis of 6-deoxypladienolide D (2014).

Scheme 16

Total synthesis of 6-deoxypladienolide D (Keaney, 2014).

Scheme 17

Final stage of the total synthesis of 6-deoxypladienolide D (Keaney, 2014).

Scheme 18

Yoo and Krische’s retrosynthetic analysis of pladienolide B (2021).

Scheme 19

Preparation of fragments required for the synthesis of pladienolide B (Yoo and Krische, 2021).

Scheme 20

The completion of the total synthesis of pladienolide B (Yoo and Krische, 2021).

Figure 4

Structural comparison of pladienolide B (2) and 10-deoxymethynolide (117).

Scheme 21

Skaanderup and Jensen’s retrosynthetic analysis (2008).

Scheme 22

Synthesis of the core structure of ent-pladienolide B (Skaanderup and Jensen, 2008).

Scheme 23

Maier’s retrosynthetic analysis of pladienolide B (2014).

Scheme 24

Synthesis of the macrocyclic core unit 143 (Maier, 2014).

Scheme 25

Preparation of the side-chain unit 144 and the final stage of the total synthesis of pladienolide B (Maier, 2014).

Scheme 26

Rhoades et al.’s retrosynthetic analysis of pladienolide A, B, and H3B-8800 (2021).

Scheme 27

Preparation of a 12-membered macrocyclic unit (Rhoades et al., 2021).

Scheme 28

Final stage of the total synthesis of pladienolide A, B, and H3B-8800 (Rhoades et al., 2021).