Total synthesis of (+)-belactosin A

Armstrong, Alan; Scutt, James N.

doi:10.1039/b316142k

Cited by 58 publications

(25 citation statements)

References 15 publications

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“…With the key intermediate 9 in hand, we next turned our attention to the synthesis of aldehyde 12 , which contains a trans ‐disubstituted‐cyclopropane moiety (Scheme ). Thus, commercially available ( S )‐2‐ethyloxirane 10 was subjected to optimized Wadsworth–Emmons cyclopropanation followed by an in situ saponification to furnish acid 11 in 82 % yield . This acid was then converted into homoallylic alcohol 11 a via a three‐step sequence involving a LiAlH 4 reduction to furnish the corresponding alcohol, a TEMPO promoted oxidation to give rise to an aldehyde and Brown allylation to set the third stereocenter.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, commercially available( S)-2-ethyloxirane 10 was subjected to optimized Wadsworth-Emmons cyclopropanationf ollowed by an in situ saponification to furnisha cid 11 in 82 %y ield. [24][25][26][27][28] This acid was then converted into homoallylic alcohol 11 a via at hree-step sequence involving aL iAlH 4 reduction to furnish the corresponding alcohol, aT EMPO promoted oxidation to give rise to an aldehyde and Brown allylation to set the third stereocenter.P rotection of the homoallylic alcohol of 11 a as its benzyl ether,f ollowed by oxidative cleavage of the terminal olefin with OsO 4 and NaIO 4 to produce the required aldehyde 12 in 26 %overall yield from 11.…”

Section: Synthesis Of Aldehyde 12mentioning

confidence: 99%

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Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

Gunasekera

Ratnayake

et al. 2016

Chemistry A European J

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A new dimeric macrolide xylopyranoside, cocosolide (1), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR, HRMS, X-ray diffraction studies and Mosher’s analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A–D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide (1) along with its [α,α]-anomer (26) and macrocyclic core (28), thus leading to the confirmation of the structure of natural 1. The convergent synthesis featured Wadsworth–Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α-selective glycosidation and β-selective glycosidation. Compounds 1 and 26 potently inhibited IL-2 production in both T-cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide (1) also suppressed the proliferation of anti-CD3-stimulated T-cells in a dose-dependent manner.

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Aldehyde 12mentioning

confidence: 99%

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

Gunasekera

Ratnayake

et al. 2016

Chemistry A European J

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“…Carbamate derivatives (1a-c) favor the With an investigation of the reactivity of compounds 3a-f in mind the behavior of the trans/cis-mixtures of 3e and 3f in the presence of BF 3 and triethylsilane was considered. Following a literature method [12] isomeric nosyl protected 3-fluoro piperidines 8e and 8f were both formed in reasonable yields. In the case of 8f an X-ray crystal structure was solved.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structural Elucidation of 1,2‐Disubstituted 3‐Fluoropiperidines

et al. 2020

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The work described details the reaction between Selectfluor® and a series of 1‐carbonyloxy and 1‐sulfonyl 2‐piperidines in order to generate 3‐fluoro‐2‐methoxypiperidines 3a–f. Their subsequent reaction with allyltrimethylsilane, in the presence of BF3 and TiCl4, is then reported. Studies involving a combination of single‐crystal X‐ray crystallography and NMR spectroscopy indicate that the allylation process is cis‐selective for both carbamate and sulfonamide variants and that optimal levels of diastereoselectivity are obtained using the N‐2‐nitrobenzene sulfonyl (2‐Ns) group. In this manner, the synthesis of a series of 2‐allyl 3‐fluoro‐substituted piperidines (5a, c–f) was achieved. The conversion of both the cis and trans‐N‐tosyl adducts (5d) into 3‐fluorinated analogues of the natural products pelletierine (10) and coniine (11) is subsequently detailed.

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“…The β-lactone unit C was prepared as shown in Scheme 2, using a procedure similar to that for the preparation of the β-lactone unit in the total synthesis of belactosin A by Armstrong et al 21 4-Methylpentanoic acid 7 was condensed with (4R)-4-benzyl-2-oxazolidinone by the mixed anhydride method using LiCl as an additivewith BrCH 2 CO 2 t-Bu/NaHMDS at -78 °C in THF to afford 9 stereoselectively. 23,24 The oxazolidinone moiety of 9 was removed by hydrolysis with LiOH/H 2 O 2 in aqueous THF to give 10.…”

Section: Scheme 1 Synthetic Plan Of 3a-6amentioning

confidence: 99%

Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure

et al. 2013

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The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to its chemical and enzymatic hydrolysis of the strained β-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered β-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its β-lactone carbonyl moiety and the conformational flexibility of the molecule.

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Total synthesis of (+)-belactosin A

Abstract: A concise first total synthesis of the antitumour antibiotic belactosin A is reported, involving coupling of beta-lactone carboxylic acid 3 with N-Ala-aminocyclopropyl alanine 11.

Cited by 58 publications

References 15 publications

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

Synthesis and Structural Elucidation of 1,2‐Disubstituted 3‐Fluoropiperidines

Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure

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