Process Development of the PDE4 Inhibitor K-34

Yanagisawa, A.; Taga, Masashi; Atsumi, Toshiyuki; Nishimura, Koichiro; Ando, Kyoji; Taguchi, Tsuyoshi; Tsumuki, Hiroshi; Chujo, Iwao; Mohri, Satoshi

doi:10.1021/op100291g

Cited by 8 publications

(10 citation statements)

References 19 publications

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“…Dihydroxy acid 3 can be synthesized in one step using a literature procedure. 71 Salicylate ester 4 was synthesized from 3 using phenol and phosphorus oxychloride in 75% yield. Acylation of 1,2,3trimethoxybenzene using 4 gave 5 in 48% yield (36% yield over the two steps).…”

Section: ■ Resultsmentioning

confidence: 99%

Integrating Metal-Catalyzed C–H and C–O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation

et al. 2018

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One major goal of organometallic chemists is the direct functionalization of the bonds most recurrent in organic molecules: C-H, C-C, C-O, and C-N. An even grander challenge is C-C bond formation when both precursors are of this category. Parallel to this is the synthetic goal of achieving reaction selectivity that contrasts with conventional methods. Electrophilic aromatic substitution (EAS) via Friedel-Crafts acylation is the most renowned method for the synthesis of aryl ketones, a common structural motif of many pharmaceuticals, agrochemicals, fragrances, dyes, and other commodity chemicals. However, an EAS synthetic strategy is only effective if the desired site for acylation is in accordance with the electronic-controlled regioselectivity of the reaction. Herein we report steric-controlled regioselective arene acylation with salicylate esters via iridium catalysis to access distinctly substituted benzophenones. Experimental and computational data indicate a unique reaction mechanism that integrates C-O activation and C-H activation with a single iridium catalyst without an exogenous oxidant or base. We disclose an extensive exploration of the synthetic scope of both the arene and the ester components, culminating in the concise synthesis of the potent anticancer agent hydroxyphenstatin.

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Section: ■ Resultsmentioning

confidence: 99%

Integrating Metal-Catalyzed C–H and C–O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation

et al. 2018

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“…This sequence gave access to the natural product in multigram quantities. Epicoccone B was synthesized starting from 2,3,4-trimethoxybenzoic acid (8), which was selectively demethylated using boron trichloride [18] and esterified to afford methyl ester 9 (Scheme 2 B). Installation of the required methyl group was achieved by Duff formylation to give aldehyde 10, followed by catalytic hydrogenation under strongly acidic conditions to furnish catechol 11.…”

mentioning

confidence: 99%

Biomimetic Synthesis of the Calcineurin Phosphatase Inhibitor Dibefurin

2014

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Dibefurin is a Ci -symmetric natural product that acts as an inhibitor of calcineurin phosphatase. A six-step synthesis of this compound is reported, which features an oxidative dimerization of the aromatic polyketide epicoccine as the key step. Dibefurin is proposed to be related to epicolactone, a complex yet racemic fungal metabolite that has recently been discovered. Attempts to access epicolactone from epicoccine and epicoccone B resulted in an unusual dimer that is formed through a hetero-Diels-Alder reaction of a para-quinone methide with an ortho-quinone.

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“…Scheme shows the synthesis of iodide 17 . Following the known protocol, 2,3,4‐trimethoxybenzoic acid ( 13 ) was converted to catechol 14 in two steps . Initial attempts at the selective mono‐benzylation of catechol 14 (BnBr, Cs 2 CO 3 , acetone, 80 °C) gave poor results, affording the dibenzylated product.…”

Section: Resultsmentioning

confidence: 99%

“…Following the known protocol, 2,3,4trimethoxybenzoic acid (13) was converted to catechol 14 in two steps. [11] Initial attempts at the selective mono-benzylation of catechol 14 (BnBr, Cs 2 CO 3 , acetone, 80°C) gave poor results, affording the dibenzylated product. However, the projected monobenzylation became possible by employing i Pr 2 NEt [12] (BnBr, cat.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of the Proposed Structure of Ardimerin, and Proposal for its Structural Revision

Nakayama

Tanzer

Kusumi

et al. 2016

Helvetica Chimica Acta

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We report the first total synthesis of the proposed structure of ardimerin, which was achieved in 14 steps starting from 2,3,4‐trimethoxybenzoic acid. The key steps include the β‐selective formation of the crucial C‐glycoside linkage and stepwise construction of the strained eight‐membered salicylide core. The synthesis revealed that the proposed structure 1 does not match the natural product. A proposal is made for reassigning the isolated natural product to the already known structure of bergenin. Interesting properties of the synthetic eight‐membered salicylides are documented, including their susceptibility toward nucleophilic ring opening and the bowl chirality.

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Process Development of the PDE4 Inhibitor K-34

Cited by 8 publications

References 19 publications

Integrating Metal-Catalyzed C–H and C–O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation

Integrating Metal-Catalyzed C–H and C–O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation

Biomimetic Synthesis of the Calcineurin Phosphatase Inhibitor Dibefurin

Total Synthesis of the Proposed Structure of Ardimerin, and Proposal for its Structural Revision

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