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We have investigated the gas-phase production of isoquinoline by performing collisional activation on benzalaminoacetal, the first intermediate in the classic solution-phase Pomeranz--Fritsch synthesis of isoquinoline. We have elucidated the reaction pathways in the gas phase using tandem mass spectrometry. Unlike the corresponding condensed-phase reaction, where catalytic proton exchange between intermediate(s) and solvent (Brønsted--Lowry base) is known to drive the reaction, the gas-phase reaction follows the "mobile proton model" to form the products via a number of intermediates, some the same as in their condensed-phase counterparts. Energy-resolved mass spectrometry, deuterium labeling experiments, and theoretical calculations (B3LYP/6-31G**) identified 27 different reaction routes in the gas phase, forming a complex interlinked reaction network. The experimental measurements and theoretical calculations confirm the proton hopping onto different basic sites of the precursors and intermediates to transform them ultimately into isoquinoline. [ABSTRACT FROM AUTHOR]

Nature synthesizes many strained natural products that have diverse biological activities. Uncovering these biosynthetic pathways may lead to biomimetic strategies for organic synthesis of such compounds. In this work, we elucidated the concise biosynthetic pathway of herquline A, a highly strained and reduced fungal piperazine alkaloid. The pathway builds on a nonribosomal peptide synthetase derived dityrosine piperazine intermediate. Following enzymatic reduction of the P450-cross-linked dicyclohexadienone, N-methylation of the piperazine serves as a trigger that leads to a cascade of stereoselective and nonenzymatic transformations. Computational analysis of key steps in the pathway rationalizes the observed reactivities. [ABSTRACT FROM AUTHOR]