Abstract
The first total synthesis of (±)-renieramycin I, which was isolated from the Indian bright blue sponge Haliclona cribricutis, is described. The key step is the selenium oxide oxidation of pentacyclic bis-p-quinone derivative (3) stereo- and regioselectively. We also report a large-scale synthesis of cribrostatin 4 (renieramycin H) via the C3-C4 double bond formation in an early stage based on the Avendaño’s protocol, from readily available 1-acetyl-3-(3-methyl-2,4,5-trimethylphenyl)methyl-piperazine-2,5-dione (8) in 18 steps (8.3% overall yield). The synthesis provides unambiguous evidence supporting the original structure of renieramycin I.
Highlights
Many tetrahydroisoquinoline antitumor natural products, such as renieramycins, saframycins, and ecteinascidins, have attracted considerable interest due to their extraordinary structures and meager availability in nature, as well as their potent antitumor activity [1,2]
Thereafter, we revised the structure of renieramycin H to that of cribrostatin 4 (2) [4,5,6], which was independently isolated from the blue sponge Cribrochalina sp. collected from reef passages in the Republic of Maldives, based on 13C NMR
The most serious problem in our previous cribrostatin 4 (2) synthesis was that 1-epi-pentacyclic alcohol (4) (Chart 1) might be formed, and the undesired stereochemistry had to be converted into the natural one at C-1 position via enolate formation through several cycles
Summary
Many tetrahydroisoquinoline antitumor natural products, such as renieramycins, saframycins, and ecteinascidins, have attracted considerable interest due to their extraordinary structures and meager availability in nature, as well as their potent antitumor activity [1,2]. Thereafter, we revised the structure of renieramycin H to that of cribrostatin 4 (2) [4,5,6], which was independently isolated from the blue sponge Cribrochalina sp. We present an alternative large-scale approach for the total synthesis of 2. This approach might yield a variety of novel analogs of cribrostatin 4 (2), as well as C3-C4 unsaturated bis-p-quinone derivatives, such as renieramycin I (1i), for detailed studies of structure activity relationships (SARs) of these classes of antitumor marine natural products
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