Enantioselective preparation of C-ring fragment of cotylenin A via catalytic asymmetric intramolecular cyclopropanation of α-diazo β-keto ester

Nagatani, Kotaro; Hoshino, Yunosuke; Tezuka, Haruka; Nakada, Masahisa

doi:10.1016/j.tetlet.2017.01.076

Cited by 11 publications

(3 citation statements)

References 18 publications

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“…Total synthesis is a potential method for providing cotylenin A and for the discovery of biologically important derivatives that are difficult to prepare from natural resources. However, despite the elucidation of its absolute structure by X-ray crystallographic analysis in 1998, the total synthesis of cotylenin A has not yet been reported, , and only one total synthesis of its aglycone, cotylenol, has been reported thus far, by Kato and co-workers …”

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confidence: 99%

Enantioselective Total Synthesis of Cotylenin A

et al. 2020

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A convergent enantioselective total synthesis of cotylenin A is described. The A-ring fragment, prepared via the catalytic asymmetric intramolecular cyclopropanation developed in our laboratory, and the C-ring fragment, prepared from a known chiral compound via a modified acyl radical cyclization, were successfully assembled by the Utimoto coupling reaction. The formidable carbocyclic eight-membered ring of cotylenin A was efficiently constructed by a palladium-mediated cyclization. All the hydroxy groups in the scaffold were stereoselectively introduced, and a modified reducing reagent, Me 4 NBH(O 2 C i Pr) 3 , has been developed. The sugar moiety fragment was prepared via three consecutive carbon−oxygen bond-forming reactions, and the glycosylation was accomplished using Wan's protocol.C otylenin A (Figure 1) was initially isolated as a plant growth regulator; 1 however, biological studies later revealed that it induces the differentiation of murine and human myeloid leukemia cells and the apoptosis of a wide range of human cancer cell lines by combined treatment with interferon-α. 2 The crystal structure of cotylenin A in a complex with 14-3-3 protein and a phosphopeptide of H + -ATPase (QSYpTV-COOH) has been reported 3 to confirm that cotylenin A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259 but not the activating interaction site, pSer621. Moreover, the combined treatment of cotylenin A with an anti-epidermal growth factor receptor antibody is reported to synergistically suppress tumor growth in vitro and in vivo, which provides a novel pharmacologic strategy for treatment of RAS mutant cancers. 4

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Enantioselective Total Synthesis of Cotylenin A

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“…The CAIMCP of α-diazo-β-keto esters is generally not enantioselective owing to the low steric effect of the ester moiety [12a, 17]. Hence, we examined the CAIMCP of α-diazo-β-keto esters bearing a bulky alcohol moiety and obtained the α-diazo-βketo ester of 2,4,6-trimethylphenol with high enantioselectivity (Scheme 11.8) [8]. Cyclopropane 18 was crystalline, and its absolute configuration was confirmed via X-ray crystallographic analysis (Scheme 11.7).…”

Section: Preparation Of the C-ring Fragment Via The Caimcp Of α-Diazo...mentioning

confidence: 99%

“…In this context, total synthesis is an effective method for supplying rare natural products and the derivatives or structural analogs of natural products that cannot be synthesized from natural products. After the structural elucidation of cotylenin A in 1998, only Kato et al [6] have developed the total synthesis of cotylenol, and an aglycon of cotylenin A and total synthesis of cotylenin A has never been reported [7,8] until our total synthesis [9,10]. The aglycone moiety of cotylenin A has a 5-8-5 carbocyclic scaffold with a quaternary asymmetric carbon at the fused ring site, a chiral tertiary alcohol at the allylic position, four consecutive chiral carbons containing trans-1,2-diols, and a four-substituted alkene bearing an isopropyl group.…”

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Overcoming Difficulties in Total Synthesis of (+)-Cotylenin A

Uwamori,

Osada,

Sugiyama

et al. 2024

Modern Natural Product Synthesis

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The total synthesis of the natural product cotelynin A, which exhibits promising anti-cancer activity, is urgently required, as its source, Cladosporium sp. 501-7W, has lost its proliferative ability. Herein, we report the first total synthesis of cotelynin A. Contiguous asymmetric carbons at the C8 and C9 positions in the B-ring of the aglycon moiety of cotylenin A are difficult to construct after the formation of the B-ring via pinacol coupling. The revised synthesis of the aglycon moiety involved the alkenylation of a methyl ketone to construct the B-ring; for this convergent synthesis, one fragment was prepared using our catalytic asymmetric intramolecular cyclopropanation, and the other fragment was obtained via the acyl radical cyclization of a known aldehyde, which was prepared by sharpless asymmetric epoxidation of geraniol and subsequent rearrangement. Radical generation using a copper catalyst and TBHP was effective for an acyl radical cyclization. The two prepared fragments were then assembled via Utimoto coupling. The α-hydroxyketone at the C8-C9 position was stereoselectively reduced with Me4NBH(O2CiPr)3, which was newly prepared in this study, and led to the successful construction of the C8-C9 1,2-diol. A structurally unprecedented sugar moiety was synthesized for the first time by terminating successive reversible acetalizations with an irreversible epoxide ring-opening reaction. Although the glycosylation of the synthesized fragments proceeded with difficulty owing to steric hindrance around the C9 hydroxy group of the aglycone, the desired product was successfully obtained under the reaction conditions reported by Wan et al.

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A Two‐Phase Approach to Fusicoccane Synthesis To Uncover a Compound That Reduces Tumourigenesis in Pancreatic Cancer Cells

Chen

et al. 2022

Angewandte Chemie

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Alterbrassicicene D (1) and 3(11)‐epoxyhypoestenone (2) were synthesised via a two‐phase approach featuring concise construction of the 5‐8‐5 tricyclic intermediate and a tandem base‐mediated epoxide opening–transannular oxa‐Michael addition cascade to forge the complex skeleton of 2. The route is scalable and we generated 15 g of the tricyclic intermediate in 8 steps from (R)‐limonene and 720 mg of the penultimate bioactive intermediate in a protecting‐group‐free manner. Our synthesis enabled the structural determination of 2 and provided materials for preliminary anticancer evaluation. The penultimate intermediate showed therapeutic potential in terms of its ability to dramatically reduce the tumourigenic potential of PANC‐1 pancreatic cancer cells according to a limiting dilution tumour‐initiating assay. Our synthetic approach will facilitate unified access to naturally occurring fusicoccanes and their derivatives for anticancer evaluation.

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Enantioselective preparation of C-ring fragment of cotylenin A via catalytic asymmetric intramolecular cyclopropanation of α-diazo β-keto ester

Cited by 11 publications

References 18 publications

Enantioselective Total Synthesis of Cotylenin A

Enantioselective Total Synthesis of Cotylenin A

Overcoming Difficulties in Total Synthesis of (+)-Cotylenin A

A Two‐Phase Approach to Fusicoccane Synthesis To Uncover a Compound That Reduces Tumourigenesis in Pancreatic Cancer Cells

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