Synthetic Studies Toward the Total Synthesis of (+/-)-Ajmaline and the Development of, Investigation into, and Application of a Phosphine-Catalyzed [4+1] Annulation

• Main Author: Blank, Brian Richard
• Format: Dissertation
• Language: English
• Subjects: chemistry, organic
• ISBN: 1321045824; 9781321045826

Several synthetic routes toward the synthesis of the indole alkaloid (+/-)-ajmaline have been explored. The retrosynthetic plan was devised around two key transformations, one being a tandem aza-Michael--Michael reaction, and the other a phosphine-catalyzed [4+2] annulation. While these approaches have not allowed for the completion of ajmaline, they have provided a great deal of insight into the chemistry of many intermediates. For example, it was discovered that following installation of the D-ring, functionalization of the tricyclic scaffold to deliver a precursor for the aza-Michael--Michael sequence was a futile undertaking. As such, the necessary functionality had to be installed prior to the [4+2] annulation. For this purpose, ethyl 3-allyl-1 H-indole- 2-carboxylate was prepared by way of a stepwise Japp--Klingemann reaction, and a subsequent Fischer indolization. Successful conversion of this compound into the N-sulfonyl imine required the employment of 2,6-lutidine to impede isomerization of the allyl moiety. This imine was converted into the tetrahydropyridine through a phosphine-catalyzed [4+2] annulation with ethyl 2-methyl-2,3-butadienoate. Cross-metathesis with methyl acrylate provided the first precursor to the desired aza-Michael--Michael reaction sequence. Unfortunately, only mono-Michael addition was observed when this substrate was employed in the reaction, providing a tetracyclic structure instead of the desired pentacyclic scaffold. As a result, we are currently pursuing tricyclic derivatives that feature either alternative Michael donors or an increased strength of the second Michael acceptor.
A phosphine-catalyzed [4+1] annulative rearrangement has been developed to prepare 3-pyrrolines from allenylic carbamates through phosphonium diene intermediates. This methodology was employed to synthesize an array of 1,3-disubstituted- and 1,2,3-trisubstituted-3-pyrrolines, including the often difficult to prepare 2-alkyl variants. A mechanistic investigation employing allenylic acetates and mononucleophiles unexpectedly unveiled that a phosphine-catalyzed [4+1] reaction previously reported by Tong might not occur through a phosphonium diene as was proposed, but rather involves multiple mechanisms working in concert to construct cyclopentene products. Consequentially, our phosphine-catalyzed rearrangement is most likely the first reaction that unequivocally forms a phosphonium diene intermediate along the reaction pathway. Concise formal syntheses of pyrrolizidine alkaloids (+/-)-trachelanthamidine and (+/-)-supinidine were completed, demonstrating the synthetic utility of this newly developed reaction.