The D1 and D2 dopamine receptors are involved with reward and motor activity. However, the D1 receptor plays a specific role in the maintenance of higher cognitive functions such as attention, executive function, and working memory. The chiral tetrahydroisoquinoline (THIQ), D1 potentiator 1, is currently in clinical trials for the treatment of Lewy Body Dementia with a possible unique mechanism of action as a D1 positive allosteric modulator. A practical synthesis of the chiral tetrahydroisoquinoline (THIQ), D1 potentiator 1, has been accomplished employing diastereoselective Pictet-Spengler methodology to access the required trans-stereochemistry. A dynamic kinetic resolution by crystallization gives high yields of a N-(phenylsulfonyl)alkyloxazolidinone that is converted to an acyl iminium ion when exposed to a variety of Lewis acids resulting in a highly diastereoselective Pictet-Spengler cyclization. An eight-step linear synthesis that starts with commercially available R-2-bromophenylalanine affords the chiral tetrahydroisoquinoline 1 in 54% overall yield.

Diastereoselective Pictet-Spengler based synthesis of a chiral tetrahydroisoquinoline D1 potentiator

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