Oxidative Nucleophilic Substitution (S_NOx) of the Benzylic Position as a Tunable Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues

Abstract

Synthetic investigations of 1,3‐dichloro‐5,6‐dicyanobenzoquinone‐mediated benzylic oxidation is reported for the synthesis of natural alkaloid analogues. Extensive explorations of the oxidative nucleophilic substitution of the benzylic position of β‐phenylethylamine derivatives and the synthesis of functionalized tetrahydroisoquinolines of ecteinascidin 743 precursors have been carried out. Starting from L‐DOPA, a tunable oxazolidinone group was installed under oxidative benzylic conditions. This derivative 13 was submitted to benzylic oxidation reactions using a wide range of carboxylic acids and subsequent chemical transformations of these compounds were attempted. Moreover, an efficient synthesis of an aromatic ketone derivative 20 was achieved and gave rise to tetrahydroisoquinoline 24 through a direct Pictet–Spengler cyclisation reaction. Subsequently, 24 was transformed into functionalized α‐amino alcohols 31a and 31b, precursors of ecteinascidin 743 analogues. In addition, in order to assess the viability of our synthetic strategy, the reaction of 24 with methyl thioglycolate was performed and the stereoselectivity confirmed by X‐ray analysis of 33a. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Synthesis of Cross-linkable 2,5-Diketopiperazine Derivatives

“…L-DOPA 1 is converted to corresponding methyl ester treated with thionyl chloride in methanol at room temperature [18]. L-DOPA-OMe hydrochloride 2 was *Address correspondence to this author at the Division of Applied Science, Graduate School of Agriculture, Hokkaido University; Kita 9, Nishi 9, Kitaku, Sapporo 060-8589, Japan; Tel/Fax: +81-11-7063849; E-mails: hasimoto@abs.agr.hokudai.ac.jp condensed with Boc-Gly 3 in the presence of DCC in acetonitrile and DMF at 0 °C.…”

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

“…In the cited study, it was also reported that the coupling of carboxylic acids 289 with 3-phenyl-2-propen-1-yl acetate ( 288 ) in the presence of DDQ gives allyl esters 290 . DDQ was used also for the acyloxylation at the benzylic position of dimethoxyarene 291 with carboxylic acids 292 to prepare esters 293 ( Scheme 64 ) [ 243 ].…”

A Synthetic Route to Highly Substituted 1,2,3,4‐Tetrahydroisoquinolines via Yb(OTf)3‐Catalyzed Diastereoselective Ring Opening of Bridged Oxazolidines: Asymmetric Synthesis of 2‐Azapodophyllotoxin

“…[4] We then pursued the development of a novel route for the efficient synthesis of highly functionalized 1,2,3,4-tetrahydroisoquinolines (THIQs), [5] a privileged structural motif that is frequently found in bioactive natural products and therapeutic agents. [6] In particular, C-4-oxidized THIQs [7] ex-hibit a wide range of biological activities. For example, 2azapodophyllotoxin (1), a nitrogen variant of podophyllotoxin, is a potent antitumor agent, [8] whereas 11-hydroxyerythratidine (2) exhibits curare-like, sedative, hypotensive, and central nerve system (CNS) depressant activities.…”

“…[12] However, a flexible and efficient synthetic route for all possible stereoisomers of C-1, C-3, and C-4 substituted THIQs has not yet been developed. [7,13] Most of the known asymmetric synthetic routes involve the Pictet-Spengler reaction or the Bis-Abstract: We herein report a robust and efficient synthetic route to highly functionalized enantiopure 1,2,3,4-tetrahydroisoquinolines (THIQs) from Garner aldehyde. We utilized the inherent chirality of Garner aldehyde through 1,2-and 1,3-/1,4-asymmetric inductions iteratively to obtain 1,2,3,4tetrasubstitued THIQs using rigid and isolable bridged oxazolidines without any external chiral sources.…”