Unexpected Formation of Naphtyl 1,3-Diaminopropan-2-ol Derivative through Azetidinium Ion Intermediate

Abstract

The cause of depression is commonly associated with a deficiency of monoamine neurotransmitters such as serotonin, norepinephrine and dopamine in the brain. Inhibition of monoamine reuptake has been an effective pharmacological treatment of various CNS disorders. As a part of our continuing efforts to develop novel antidepressants for multiple therapeutic utilities, we designed diaminopropan-2ol 1 through structure analysis and molecular modification and of currently marketed reuptake transporter based antidepressants. The retrosynthetic route of the designed diaminopropan-2ol 1 is illustrated in Scheme 1. The diaminopropan-2-ol 1 would be synthesized from oxirane 3 via a diol intermediate 2 by nucleophilic attack of the amine (HNR1R2) to epoxide moiety. The oxirane 3 would be prepared from commercially available aldehyde 5 by the Wittig reaction, followed by epoxidation of the double bond of the resultant olefin 4. The oxirane 3 is a key intermediate to accomplish the exploration of novel antidepressants. The epoxide is susceptible to the ring opening reaction with various nucleophiles, and the resulting hydroxy group would bear diverse substituents. The overall synthetic route is summarized in Scheme 2. The Wittig reaction of aldehyde 5 with ethyl 2-(triphenylphosphoranylidene)acetate in methylene chloride at room temperature afford the ester 6 in quantitative yield. The reduction of the ester 6 by the treatment with diisobutylaluminium hydride (DABAL-H) in methylene chloride under a nitrogen atmosphere at –78 oC provided the corresponding alcohol 4. Epoxidation of the double bond in 4 by reaction with m-chloroperbenzoic acid (m-CPBA) in methylene chloride at room temperature proceeded smoothly, resulting in oxirane 3. The initial attempt for the synthesis of our target compound