JACS: David sarlah research group of University of Illinois completed the total synthesis of Toona type triterpenoids

Rhabdastrelicacid a (1) and stelletin e (2) are representative members of Toona type triterpenoids, which have been paid more and more attention due to their remarkable antitumor properties (Figure 1) At present, stellertins (2 - 4) has become a potential lead compound for targeted therapy, while stellerin riboside (5) is a rare glycosylated isotoona, which has high cytotoxicity to L5178Y mouse lymphoma cell line Rhabdastrelicacid a (1) and stelletins (2 - 4) can induce apoptosis at nanomolar level in human colon, leukemia, glioblastoma and non-small cell lung cancer cell lines, interfere with PI3K / Akt / mTOR growth factor signal transduction, cause G1 phase arrest and autophagy cell apoptosis, and show the least toxicity in healthy tissues Due to the scarcity of these compounds, the mechanism of apoptosis, molecular target and pharmacophore structure have not been clarified Therefore, it is urgent to establish an effective synthesis strategy for toonane triterpenoids, and provide enough samples for biological research Recently, the David sarlah group of the University of Illinois constructed the trans syn trans parent nucleus of Toona type triterpenoids and completed the first synthesis of (±) - rhabdastrillic acid A (1) and (±) - stelletin e (2), which was published in J am Chem SOC (DOI: 10.1021 / JACS 9b08487) (photo source: J am Chem SOC.) synthesis strategy of isotoonane triterpenes (Figure 2): in order to obtain a large number of isotoonane compounds with different side chain structures, the author plans to construct stereochemistry at the BC ring junction, and then cross couple the tricyclic parent nucleus with electrophilic reagent However, the "boat like" conformation with tension in the B-ring makes its structure difficult to construct, and the conventional polyene cyclization strategy is also difficult to obtain this stereochemistry Therefore, the author chose an indirect synthesis method: firstly, C-ring was constructed by the stereoselective cycloisomerization of alkyne 6 (rautenstrauch rearrangement) and the quaternary carbon center was introduced at the C-8 position; then, specific stereochemistry was introduced by the asymmetric reduction of ketene 7; alkyne 6 could be synthesized by bicyclic skeleton 9, and 9 could be synthesized by the commercial geranyl acetone (10 ）It is prepared by cyclization of polyene (Figure 2a) Rautenstrauch rearrangement is carried out by means of a spiral transition state, which transfers the stereoisomerism from the orthoalkynyl carbon (C-11 position) to the newly formed stereocenter (C-8 position) (photo source: J am Chem SOC.) specific synthesis route (Figure 3): the author took geranyl acetone (10) as the starting material, and obtained nitrile 11 through improved van leusen reduction cyanidation and selective epoxidation of end ene, and then constructed bicyclone 9 through Ti (III) - mediated reduction free radical polyene cyclization and silicon ether protection After carbonylation of α, β - unsaturated aldehydes with lithium acetylene, the key cycloisomerization precursor, enyne 6, was obtained by in-situ protection of Neopentyl acid ester In the presence of selectfluor ®, the author treated 6 with Au (I) catalyst to construct C-ring α - fluoroenone, and then reacted with NH 2 nhts to obtain α - fluorohydrazone 12 in situ 12 in triethylamine / methanol solution, azoene 13 (Figure 3B) is produced Then, under standard conditions, the author selectively added hydrogen atoms to the desired side through the inverse ene rearrangement of allyldiazene 14 to obtain enolmethyl ether 15 After reduction zirconization of enol methyl ether, it was cross coupled with acetyl chloride under the catalysis of copper to obtain 16 After borohydride oxidation, in-situ deprotection and oxidation, trione 17 was obtained, which was a single isomer Its structure was confirmed by single crystal X-ray diffraction analysis Subsequently, 17 was brominated with Vilsmeier reagent to obtain electrophilic reagent 22, which is a single isomer After obtaining the mother nucleus of isotoonane triterpenoids, the author turned his attention to the synthesis of polyene side chains and the later cross coupling Firstly, the side chain segment 20 was obtained by HWE alkylation of stannedialdehyde 18 and phosphonate 21, and the methyl ester of rhabdastrillicacid a was assembled by stile coupling of vinyl bromide 22 and stantane 20 The ratio of rhabdastrillicacid a to the isomer methyl ester of stelletin e was 8:1 The former is saponified quantitatively to obtain (±) - rhabdastrillic acid A (1), or hydrolyzed by ester to obtain (±) - stelletin e (2) and (±) - rhabdastrillic acid A (1:1.9) It is reported that the isomerization of C-13 and C-14 olefins (i.e 1 ⇌ 2) occurs easily when Toona is exposed to visible light Therefore, 2 (33%) can be obtained by irradiating 1 with light, and then the remaining 1 (63%) can be recovered and transformed After two cycles, the total yield of 2 can be increased to 53% (photo source: J am Chem SOC.) conclusion: David sarlah's group has completed the first full synthesis of ± - rhabdastrillic acid A and (±) - stelletin e from commercial Citronellyl acetone through 14 linear steps The synthesis is characterized by cyclization of reductive free radical polyene, oxidative rautenstrauch ring isomerization and polarity reversal α - substitution of toluenesulphonylhydrazone by in-situ reduction conversion This late cross coupling strategy with polyunsaturated side chains developed by the authors provides a reference for the synthesis of many challenging marine triterpenoids.