A new synthetic approach to 1-(hydroxymethyl)-8-methoxy-1,2,3,4-tetrahydroisoquinolin-4-one

Williams, Robert M.; Ehrlich, Paul; Zhai, Weixu; Hendrix, James A.

doi:10.1021/jo00388a056

Cited by 43 publications

(19 citation statements)

References 2 publications

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“…To test the optical purity of these compounds, the lithium salts of the α-keto acids 1a , c were reductively aminated using ammonium acetate and sodium cyanoborohydride in methanol to produce N-protected DAP derivatives (Figure ). Deprotection by hydrogenolysis or acid-catalyzed hydrolysis afforded mixtures of DAP stereoisomers which were converted to bis-Marfey derivatives and analyzed by reverse phase HPLC.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Novel Substrates and Inhibitors of N-Succinyl-ll-diaminopimelate Aminotransferase (DAP-AT) from Escherichia coli

et al. 1996

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N-Succinyl-ll-diaminopimelate aminotransferase (DAP-AT) (EC 2.6.1.17), a key enzyme in the bacterial pathway to l-lysine, was purified to near homogeneity (1500-fold) in five steps from wild type Escherichia coli ATCC 9637. This pyridoxal phosphate (PLP) dependent enzyme has a molecular weight of 39.9 kDa, appears to form an active homodimer, and uses l-glutamate as the amino group donor for its substrate, N-succinyl-α-amino-ε-ketopimelic acid (1a) (K m = 0.18 ± 0.04 mM, k cat = 86 ± 5 s-1). Progress of the reaction is monitored by spectrophotometric observation of decrease in NADPH concentration at 340 nm in a coupled enzyme assay with l-glutamate dehydrogenase (EC 1.4.1.4). Stereochemically pure 1a was synthesized as its trilithium salt by ene reaction of methyl glyoxylate with methyl N-succinyl-l-allylglycinate (4a) followed by hydrogenation of the double bond, Dess−Martin oxidation of the alcohol, and careful lithium hydroxide hydrolysis. Similar approaches allowed synthesis of a series of substrate analogues 1b − g having different N-acyl substituents, as well as derivatives missing the carboxyl group or the amide functionality (13 and 17, respectively). Compounds lacking the keto functionality (18a, 18c, and 19) were also prepared. Assay of DAP-AT shows that the enzyme has quite strict requirements for substrate recognition, but it will accept compounds with an aromatic ring in place of the terminal succinyl carboxyl group in 1a (e.g. N-Cbz-α-amino-ε-ketopimelic acid (1c)). Reaction of substrates 1a,c with hydrazine hydrate followed by NaCNBH3 reduction gives 2-(N-(succinylamino))- (20a) and 2-(N-Cbz-amino)-6-hydrazinoheptane-1,7-dioic acids (20c), respectively. These are the most potent slow-binding inhibitors of any DAP-metabolyzing enzyme reported so far (K i* for DAP-AT: 20a is 22 ± 4 nM; 20c is 54 ± 9 nM).

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Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Novel Substrates and Inhibitors of N-Succinyl-ll-diaminopimelate Aminotransferase (DAP-AT) from Escherichia coli

et al. 1996

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“…The resultant phenol was protected as its tert ‐butyldiphenylsilyl ether 11 . Lithiation of the bromine function followed by coupling of the organometallic agent with the Weinreb amide of benzyloxyglycolic acid yielded 12 11. Asymmetry was introduced by submitting ketone 12 to Noyori transfer‐hydrogenation conditions, thereby providing homochiral 13 12.…”

Section: Methodsmentioning

confidence: 99%

Stereospecific Formal Total Synthesis of Ecteinascidin 743

et al. 2006

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“…After lithiation of 109 , treatment with the Weinreb amide derivative gave the ketone 110 . 88 Asymmetric reduction of 110 was accomplished by the combination of Noyori transfer-hydrogenation reaction 89 and treatment of 111 with DPPA to give azide 112 . After hydrogenation of azide of 112 , reductive amination provided the two-carbon homologated product.…”

Section: Synthetic Studies Of Et-743mentioning

confidence: 99%

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

et al. 2015

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The Ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, Ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed.

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A new synthetic approach to 1-(hydroxymethyl)-8-methoxy-1,2,3,4-tetrahydroisoquinolin-4-one

Cited by 43 publications

References 2 publications

Synthesis and Evaluation of Novel Substrates and Inhibitors of N-Succinyl-ll-diaminopimelate Aminotransferase (DAP-AT) from Escherichia coli

Synthesis and Evaluation of Novel Substrates and Inhibitors of N-Succinyl-ll-diaminopimelate Aminotransferase (DAP-AT) from Escherichia coli

Stereospecific Formal Total Synthesis of Ecteinascidin 743

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

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