Ye Tao research group of Shenzhen Graduate School of Peking University completed the synthesis of iriomotolide-2a C (6) - C (28) fragment

The author: iriomotelide-2a (1), a new macrolide compound (J hetercocycles, 2015, 91, 265), was isolated from marine Amphidinium sp dinoflagellate (hya024 strains) near Okinawa Island, Japan by Tsuda research group in 2015 The structure of the compound has the following characteristics, including 11 chiral centers, 3 hydroxyl groups, 2 internal double bonds, 1 external double bond and two adjacent tetrahydrofuran rings The relative and absolute stereochemistry of the compound is mainly determined by NMR, including Mosher method and coupling constant These compounds have significant cytotoxic activity on human B-lymphoma DG75 cells and human cervical adenocarcinoma HeLa cells, with IC 50 values of 6 and 30 ng / ml, respectively The unique biological characteristics and structural complexity of marine natural products of iriomotelides have always encouraged chemists to study their total synthesis Ye Tao research group of Shenzhen Graduate School of Peking University has been devoted to the synthesis of bioactive marine natural products and their derivatives / analogues In 2010, the large ring parent nuclear structure of iriomotelide-1a was synthesized, 4773), and then complete the synthesis of amphidinins E and F and EPI amphidinin f (org Chem Front 2018, 5, 629) Recently, the research group published the research work on the synthesis of iriomotelide-2a C (6) - C (28) fragment of marine natural product on organic letters (DOI: 10.1021/acs.orglett 8b00542) (source: Organic letters) based on the structural analysis of molecules, the author proposed the inverse synthesis analysis (scheme 1) as shown in the figure: firstly, the C5-C6 double bond of iriomotelide-2a (1) was cut off, and then the closed-loop was realized by ruthenium catalyzed olefin metathesis (RCM), and then the deprotection could be obtained from the precursor (2) The ester bond of compound 2 was cut off and then produced from key intermediate 3 by Yamaguchi esterification Compound 3 can be constructed by coupling vinyl iodine 4 with Suzuki miyaara of alkyl borate, a derivative of alkene 5 (source: Organic letters) the specific synthesis route is as follows: first, the synthesis of key segment 4 (scheme 2), using commercial iodide 6 as the starting material, through cesium trifluoroacetate replacement, diethylamine cracking trifluoroacetate to obtain the corresponding single non enantiomer alcohol 7 Then, vinyl ether 11 was prepared by DES Martin oxidation, condensation of Evans aldehyde alcohol induced by cofactors, reduction and removal of cofactors, selective p-toluenesulfonylation, and then treated with ethyl propionate in the presence of N-Methylmorpholine Iodide 12 was obtained by replacing toluene sulfonate with iodine In the presence of triethylborane, tris (trimethylsilyl) - silane was used to treat 12, and a single non enantiomeric cyclization product 13 was obtained in 99% yield Then, after deprotection, dibal-h reduced ethyl ester, DDQ cracked PMB ether, BIS TBS protected glycol, and 2, 5-dichlorobenzyl, DESs Martin oxidizes 14 primary alcohols, and then reacts the resulting aldehydes with seyferth Gilbert reagent to obtain alkyne 16 Methyl iodine was used to methylate the terminal alkyne and selectively remove the strong base TBS to obtain the primary alcohol 17 The alkyne 17 was hydrogenated and iodized to obtain vinyl iodine 18 Then, the aldehydes and (methoxymethyl) triphenylphosphonium inner onium salt were monocarbon homologated, the alkanol ether was hydrolyzed in acid, and the aldehydes were Wittig enolized to obtain the key fragment 4 (source: Organic letters) another key segment of olefin 5 synthesis (scheme 3), using (R) - 2-aminobutyric acid as the starting material, after diazotization, methylation, conversion to α - hydroxymethyl ester 19, conversion to Weinreb amide, reaction with ethyl magnesium bromide to get the corresponding ethanone 21 Then, through the condensation reaction with aldehydes 22 and Paterson aldehydes alcohol mediated by boron, a single non enantiomer alcohol 23 was prepared The correct configuration of the generated hydroxyl was confirmed by Mosher method After the hydroxyl protection of TBS, ether 24 was obtained Then the BZ protection group was removed and compound 25 was obtained by TBS protection Finally, ketone 25 was converted to its corresponding alkene 5 by Peterson olefin alkylation (source: Organic letters) fragment efficient connection: after obtaining two key intermediates 4 and 5, start to try the key coupling reaction (scheme 4) of the whole route Firstly, the alkene 5 was boronized by 9-boradiecyclo [3.3.1] nonane (9-BBN), and then it was connected with vinyl iodide 4 by Suzuki coupling reaction catalyzed by palladium The C (6) - C (28) fragment 3 in iriomotelide-2a containing 10 chiral centers was obtained (source: Organic letters) conclusion: the author designed a simple and efficient aggregation synthesis route, and completed the synthesis of C (6) - C (28) fragment (3) in iriomoteilide-2a (1) C (6) - C (18) fragments were prepared by the free radical cyclization of vinyl ether intermediates and palladium catalyzed hydrogenation / iodization of stannic alkynes Paterson aldol reaction and Peterson alkylation were used to construct C (19) - C (28) fragments Finally, the connection of C (6) - C (18) and C (19) - C (28) fragments was completed by Suzuki miyaara coupling reaction Professor Ye Tao