i The Improved Isopropylation of a Ketalaldehyde by Diisopropylzinc and a Ligand Catalyst
Walsh, Sean P.
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Squalamine is an aminosterol that naturally occurs in spiny dogfish sharks and exhibits antibiotic and antiviral activity. The demand for squalamine has acutely increased as its potential to combat the symptoms of Parkinson’s disease has shown promising results in recent human trials.2 Since obtaining natural squalamine involves killing spiny dogfish sharks, it is unsustainable and ecologically destructive. Therefore various economical synthetic routes have been developed. A common intermediate to the production of squalamine is a ketalaldehyde, which undergoes enantioselective isopropylation, and has afforded moderate to poor yield resulting in an increase to the cost of synthetic squalamine production. This study aimed to improve the yield of the step that converts the ketalaldehyde into the C24-isopropylated intermediate. The C24-isopropyl adduct was formed from an enantioselective isopropylation of the ketalaldehyde with diisopropylzinc and is facilitated by a β‐dialkylamino alcohol ligand catalyst, (1R,2S)-2-(Dibutylamino)-1-phenyl-1-propanol. The result was an 88.8% yield by HPLC, or a 74% isolated yield through trituration on a 0.191 mole scale. The side product formation has been reduced, which largely accounts for the increase in yield. The reaction conditions explored in this study include reaction temperature and relative reactant concentrations.