CBG online store epidemic prevention zone is now on line with limited time offer
Click "read original" for details
Curvulamine (1, figure 1) is a rare bipyrrole alkaloid isolated from the fungal strain Curvularia sp. ifb-z10 by Tan Renxiang research group of Nanjing University in 2014. Biologically, 1 showed excellent inhibitory activity against a variety of gram-positive and Gram-negative bacteria. However, curindolizine (2), a natural product of tripyrrole, lacks the above characteristics but has anti-inflammatory activity. Based on the biological activity and characteristic chemical structure of curvulamine, the team of Thomas J. Maimone of the University of California, Berkeley, United States, started to study the total synthesis of curvulamine. Starting from the starting materials on the market, they completed the first total synthesis of (-) - curvulamine by using 10 steps. The results were published in J. am. Chem. SOC. (DOI: 10.1021 / JACS. 9b12546). Biosynthesis studies have shown that pyrrole containing alkaloids can be derived from the coupling of 10-C fragments (see 3), which are derived from alanine and 4 units of acetyl coenzyme A (Figure 1). The challenge of synthesis 1 lies in the construction of a highly crowded five ring skeleton with six consecutive chiral centers, four of which contain c-heteroatom bonds. In addition, the presence of two kinds of electron rich pyrrole, especially vinyl pyrrole, is sensitive to acid and oxidation, which limits a variety of chemical reactions. According to the reverse synthesis analysis (Figure 1), curvulamine (1) can be obtained by diketone 4 through the 2-C nucleophilic reagent cutting and redox operation, and then by pyrrolo [1,2-a] azacycloheptene-7-one 5 and pyrrole 6 through the envisaged bond pairing to construct tetracyclic 4.
(image source: J. am. Chem. SOC.)
Firstly, the (E) - 4-methoxy-3-butene-2-one (8) and BOC protected pyrrole-7 were acetalded to form diene-9, and then in the presence of DBU, they were isomerized and aromatized at 150 ℃ to form bicycles-5. Scheme 1A: 2-bromopropionic acid methyl ester 10 and 2-methyl pyrrole sodium salt react with SN2 to get aldehydes, which are then converted into cyanohydrin 11, which is a mixture of non enantiomers (2.4:1). It does not need to be purified for the next reaction.
(scan or long press the QR code in the figure, and then go to the page of epidemic prevention area after identification)
After obtaining fragments 5 and 11, the author tried to construct scheme 1b, and found that the anion of cyanohydrin 11 can selectively add with heteroaromatic ring 5 to construct the first C-C bond (Figure 1); after adding cyanohydrin anion, the enol produced by quenching with NIS was used to obtain iodide 12.
(image source: J. am. Chem. SOC.)
The iodine atom of intermediate 12 provides a variety of potential ways for the construction of six membered rings in 4 (Table 1). When the electron rich pyrrole was used to replace the iodine atom or palladium catalyzed coupling, no target product was obtained. Although smi2 can rapidly reduce C-I bond without cyclization, the method based on Photoredox is more promising. Both iridium and ruthenium based photocatalysts can promote the cyclization to 13, accompanied by the deprotection product 14. Through the control experiment, the author found that 12 irradiation in methanol can promote cyclization and in-situ cyanohydrin deprotection. Finally, the yield of 13 g can be obtained by using t-BuOH with less nucleophilic as solvent and enough radiation. The structure of product 16 was confirmed by single crystal X-ray diffraction (scheme 1b). Because of the unexpected ketone preferred reaction, the correlation between the polycyclic hemiacetal 16 and curvulamine was not found. In addition, the structure also confirmed that the methyl group has the incorrect stereochemistry as shown in 1. However, the acetal 17 was obtained by treating 13 with an excess of ethyl vinyl ether lithium salt.
(image source: J. am. Chem. SOC.)
After obtaining 17, the author studied the epimerization of the chiral center of the mismatched methyl group, and thought that the minimization of 1,3-allylic tension between C-1 and C-10 methyl group was beneficial to the desired configuration. The isomerization mixture 18 (2.3:1) of hemiacetal was obtained by heating 17 with alkali in 85% yield, and the isomer mixture 19 and 20 of thiocarbonate were obtained by activation of bridgehead hydroxyl. Finally, 19 was deoxidized and hydrolyzed to methyl ketone 22 in acid condition. For the enantioselective reduction of (±) - 22, the author has tried various reduction conditions (NaBH4, DIBAL, LiBH (ET) 3, LiAlH4, Zn (OTF) 2, LiBH4). Finally, the author reduced (±) - 22 with CBS in 90% yield to obtain a separable mixture (1:1) of (- - 1 (97% ee) and (+ - 23 (94% ee). Conclusion: Thomas J. Maimone group completed the first full synthesis of curvulamine (1), a natural product of bipyrrole, through ten steps reaction, so that 1 and 23 enriched with enantiomers can be prepared for in-depth antibacterial activity research. In addition, by using the homologues of intermediate 11 and intermediate 16, the unnatural derivatives with structural diversity can be further prepared.
Original text (scan or long press QR code, and then go to the original page after identification):
Safe return to work and safe life CBG online store epidemic prevention zone is now online
Limited time offer: 30 for every 1000, 80 for every 2000. Please click "read the original" below
● chem. SCI.: Michael group, University of Washington realizes the olefin diamine catalyzed by selenophosphamide
● angelw: asymmetric synthesis of chiral allyl alcohol by catalyzing the rearrangement of [2,3] - meisenheimer
ACS & nbsp; catalyst.: PD catalyzed electrooxidation of C-H amination to construct pyridine [1,2-a] benzimidazole ● Angel: complete synthesis of tiacumicin B by hydrogen bond oriented highly selective β - glycosylation