Abstract
The spliceostatins/thailanstatins are a family of linear peptides/polyketides that inhibit pre-mRNA splicing, and as such act as potent cytotoxic compounds. These compounds generally contain 9 stereocenters spread over a common (2Z,4S)-4-acetoxy-2-butenamide fragment, an (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran fragment and a terminal oxane ring joined by a dienyl chain. Due to the impressive antitumor properties of these compounds, along with their complex structure, a number of total syntheses have been reported. This review will compare the synthetic strategies reported through the end of 2019.
Highlights
The spliceostatins/thailanstatins (Figure 1) are a family of linear peptide/polyketide natural products isolated from the bacteria Burkholderia sp
These compounds are of interest due to their ability to bind to a subunit of the human spliceosome, splicing factor 3b [6], which inhibits pre-mRNA splicing, and as such act as potent cytotoxic compounds
A review of the discovery, target identification, and biological applications of the compounds that exhibit these binding characteristics has been published [7]. These compounds all contain a common (2Z,4S)-4-acetoxy-2butenamide fragment, appended to an-2,3,5,6-tetrasubstituted tetrahydropyran fragment. The members of this family primarily differ with respect to the terminal oxane ring which is attached to the common fragments by a dienyl chain
Summary
The spliceostatins/thailanstatins (Figure 1) are a family of linear peptide/polyketide natural products isolated from the bacteria Burkholderia sp. Syntheses of the C-1–C-6 segment of spliceostatin E (10) The Ghosh group’s synthesis of the C-1–C-6 segment of spliceostatin E (10) relied on a Cu-catalyzed Grignard addition to tert-butyldiphenylsilyl-protected (R)-glycidol, followed by the generation of the mixed acetal 113 (Scheme 18) [33]. Fragment coupling via Wittig and Julia olefinations Kitahara’s group utilized Wittig and modified/one-pot Julia olefination [41] reactions to fashion the dienyl segment, joining the two tetrahydropyran fragments As their 2nd-generation synthesis was more efficient, this will be described (Scheme 19) [9]. A protecting-group adjustment finalized the synthesis of 124 These authors found that switching the sulfone and aldehyde functionalities, i.e., an olefination of the aldehyde generated by the oxidation of 77 with Kitahara’s sulfone 119, proceeded less efficiently (22% yield). Scheme 24: Nicolaou syntheses of thailanstatin A and B (7 and 5) and spliceostatin D (9) via a Pd-catalyzed Suzuki–Miyaura coupling
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