Biomimetic Phosphate-Catalyzed Pictet-Spengler Reaction for the Synthesis of 1,1'-Disubstituted and Spiro-Tetrahydroisoquinoline Alkaloids

Abstract

Tetrahydroisoquinoline (THIQ) alkaloids are an important group of compounds that exhibit a range of bioactivities. Here, a phosphate buffer-catalyzed Pictet-Spengler reaction (PSR) using unreactive ketone substrates is described. A variety of 1,1'-disubstituted and spiro-tetrahydroisoquinoline alkaloids were readily prepared in one-step and high yields, highlighting the general applicability of this approach. This study features the role of phosphate in the aqueous-based PSR and provides an atom-efficient, sustainable route to new THIQs.

Figure 1

Selected 1,1′-spiro tetrahydroisoquinoline alkaloids.

Scheme 1. (a,b) Reported Lewis Acid-Catalyzed PSRs with Ketones; (c) Previous Aqueous Phosphate-Mediated PSRs with Aldehydes; (d) PSRs with Ketones Reported in This Work

Scheme 2. Application of the Phosphate-Catalyzed PSR to Synthesize 1,1′-Disubstituted and Spiro-THIQ Alkaloids

Typical reaction conditions: dopamine 5 (15–25 mM), ketone (20–150 mM), and sodium ascorbate (1.0 equiv relative to dopamine or the corresponding phenethylamine) were reacted together on a 1 mL scale in 0.3 M KPi, pH 9 and methanol (50% v/v of methanol and ketone combined) at 70 °C. Small scale reactions were performed in duplicate or triplicate. Yields were determined by ¹H NMR spectroscopy with an internal standard (maleic acid), and also by HPLC analysis (see Supporting Information, Table S5 for HPLC retention times) for several examples to confirm the data. 10 equiv of the corresponding ketones were used. 50 equiv of the corresponding ketones were used. All products were isolated (yields are in brackets) either from these small scale reactions or larger reactions and purified, using the acid–base extraction method or preparative HPLC, for characterization purposes.

Scheme 3. Application of the KPi-Catalyzed PSR with 27 in a Cascade Reaction