Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines

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We conceptualized a methodology development with biologically relevant chemical moieties such as pyridine, nicotinates, nicotinic acid/amide, based on our experience in privileged substructure-based diversity-oriented synthesis (pDOS) and literature survey about late-stage chemical synthesis. We knew that the popular Bohlmann-Rahtz related pyridine synthesis and other multi-component reactions already pave the way to a large variety of substituted nicotinates.1-2 However, the biosynthesis of Vitamin B3, which involves the ring-opening of indoles as a crucial step for the formation of nicotinic acid, soon caught our attention. This biosynthetic process of Vitamin B3 stimulated us to develop a new methodology to incorporate Vitamin B3 into pharmaceutically active anilines. However, we were puzzled about fixing the nicotinate scaffold and distinguishing this amid classical known methods (but we got a clue where the C2 and C6 substitutions are inevitable in all classical approaches!).

Unfortunately, both our reactants (N-acetyl 3-formyl indole and β-aminoacrylate), initially selected to simulate N-formyl kynurenine formation, were found incompatible with the reaction condition (See supplementary Figure 1-3). It was quite challenging to find a suitable alternate for β-aminoacrylate. Still, we came up with an idea for in situ generations of β-aminoacrylate with propiolates, which changed this project's fate. Initially, we were afraid to treat propiolates with (aza)indole bearing free -NH, which might end up with Michael addition between free -NH and propiolates. To our pleasant surprise, we observed the smooth transformation of (aza)indole bearing free -NH to vitamin B3 conjugated with anilines/aminopyridines, which greatly expanded the scope of this chemistry. While investigating the reaction's scope, we prepared vitamin B3 conjugated with (hetero)arylamines containing bromo and boronic ester moieties, valuable intermediates for further diversification via cross-coupling strategies. Besides, our methodology allows the late-stage conjugation of vitamin B3 to aniline/aminopyridine pharmaceuticals via retrosynthetic analysis with the corresponding (aza)indole precursors. Although propiolate synthesis was difficult for the complex molecules, dehydration made propiolate synthesis feasible. Thanks to Dean stork apparatus! 

We also pursued the mechanistic investigation to reveal the actual reaction mechanism and faced many hurdles. We initially postulated Path A based on literature, especially connecting to Bohlmann-Rahtz pyridine synthesis (see Fig. 5 in the manuscript). However, during our lab meeting (Thanks to all lab members), we challenged every experimental evidence to match our postulated mechanism. These internal discussions led us to design new experiments with deuterated compounds. We were surprised to get the substantial evidence supporting Path B, which now provides more insights about reactivity in aminoacrylates and explores new pyridine synthesis reactions.

Here, we have shared a few of our experiences, including failures, with our enthusiastic readers. Hopefully, this unique approach of conjugating vitamin B3 with (hetero)arylamines and theme-behind can provide new insight into the scientific community.

References;

(1) Bagley, M. C., Glover, C. & Merritt, E. A. The Bohlmann-Rahtz pyridine synthesis: From discovery to applications. Synlett 2459–2482 (2007)

(2) Allais, C., Grassot, J. M., Rodriguez, J. & Constantieux, T. Metal-free multicomponent syntheses of pyridines. Chem. Rev. 114, 10829–10868 (2014).

Seung Bum Park

Professor, Seoul National University

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