82 Deaminative Ring Contraction Toward Polycyclic (Hetero)Aromatics and Santiagonamine

Faculty Mentor: Andrew Roberts (Chemistry, University of Utah)

Abstract:

Polycyclic (hetero) aromatic structural motifs are commonly found in bioactive natural products, especially in plant-produced secondary metabolites. To address limitations in known strategies to access these important motifs, the Roberts group has developed a strategy to synthesize substituted pyridyl-bearing ortho-fused aromatic molecules from commercially available building blocks. The blocks are assembled and transformed in three steps that can be described as tertiary amine formation (‘build’), reductive cyclization (‘cyclize’), and deaminative contraction (‘contract’) events (Fig. 1).^[1][2] In the first step, a reductive amination or amine alkylation reaction is used to build a tertiary amine from a substituted benzaldehyde or substituted benzyl bromide (formed in situ), respectively.^[3] Next, this tertiary amine is reductively cyclized^[4] to form a seven-membered biaryl-linked dihydroazepine. Finally, the ‘azepine ring’ is contracted by a deaminative process to form the targeted three-ring aromatic. To demonstrate applications to more advanced targets, we are using the build-cyclize-contract strategy to access substituted phenanthrenes^[5] and the bioactive natural product santiagonamine 1 (Fig. 2).

To display of the broad application of the build-cyclize-contract strategy, we have completed a substrate scope of substituted phenanthrenes.^[6] A variety of substrates were isolated with moderate to high yields. I personally completed 3-methylphenanthrene, 3,4- dimethoxyphenanthrene, 3-methoxyphenanthrene, 4-methoxyphenanthrene, and 3- fluorophenanthrene, shown in Fig. 2. This work allowed me to build confidence with the strategy and begin work on santiagonamine 1, a more complex target (Fig. 2).

Santiagonamine, a bioactive natural product defined by its isoquinoline-containing core, exhibits wound healing properties.^[7] In 2007, Kelly and coworkers completed the only total synthesis of santiagonamine,⁶ where they joined two functionalized aromatic rings using a Pd- catalyzed Ullmann coupling and converted the biaryl intermediate into the substituted isoquinoline core using a photocyclization reaction (Fig. 3).^[8] The efficiency of this concise strategy (nine linear steps) is hampered by the subsequent three post functionalization steps required to install the N,N– dimethylphenethyl moiety, through benzylic bromination, a Stille cross coupling, hydroxylation of the alkene, and finally reductive amination. Overall, the length of Kelly’s synthesis (12 linear steps from commercial isovanillin and overall yield of 2.6%) prohibits a more thorough structure- activity relationship studies.

Our proposed multi-step synthesis aims to build santiagonamine via the key Reissert intermediate (Fig 4). This route focuses on early functionalization and preservation of the N,N– dimethylphenethylamine throught utilization of the build-cyclize-contract strategy. Another major goal of this route is step 6 as it will require development of a modified Pictet–Spengler reaction not previous seen to convert macrocycle 10 to biaryl-linked azepine 11. This step highlights the creativity utilized to develop the proposed synthesis, as well as the flexibility of our amine- templated strategy toward novel chemistry.

Concurrent with development of my natural product target, we have completed a substrate scope of substituted phenanthrenes⁴ that aid in the display of the broad application of the build, cyclize, contract method. 16 substrates were isolated with moderate to high yields; I personally completed 3-methylphenanthrene, 3,4-dimethoxyphenanthrene, 3-methoxyphenanthrene, 4- methoxyphenanthrene, and 3-fluorophenanthrene, shown in Fig. 4.

The utilization of the build-cyclize-contract strategy toward substituted phenanthrenes and complex natural products advances previous developments from the Roberts laboratory, and emphasizes the broader impact of a standardized synthesis route for a collection of more complex polycyclic compounds.