Zincke aldehyde

Scheme 4.6 The common core structure of many indole monoterpene alkaloids might be accessed through a tetracyclic Zincke aldehyde-derived building block...

Scheme 4.10 Unexpected thermal rearrangement of Zincke aldehydes leads to some interesting reactivity (DNP = 2,4-dinitrophenyl)...

In the course of our successful synthesis, we identified several limitations of our new method and associated strategy (1) the harsh conditions of the bicyclization reaction do not tolerate base-sensitive functionality such as vinyl halides (2) post-cyclization manipulations such as iododesilylation reactions are complicated by the sensitive/ reactive functionality of the products (a,p-unsaturated aldehyde, indoline, etc.) and (3) the incorporation of the required functionality into the Zincke aldehyde requires the synthesis of a complex tryptamine derivative, resulting in a lengthy, non-convergent route. In order to develop a concise route to strychnine, we would have to address each of these issues, and a straightforward solution to obviate all of these is described below. 

Vanderwal and coworkers [39] have recently reported an interesting method for the synthesis of polycyclic lactams from the pericyclic cascade reactions of Zincke aldehyde derivatives (5-amino-2,4-pentadienals). Under thermal conditions, Zincke aldehydes 89 are converted to Z-ot,p,y,5-unsaturated amides 90 via a cascade of pericyclic rearrangements [40] (Scheme 25). 

Starting with an indole-containing Zincke aldehyde substrate 91, the above authors [39] were able to effect a similar pericyclic rearrangement, followed by an intramolecular cycloaddition reaction of the resulting diene-amide 92, thus accessing a tetracyclic product 93 which could possibly serve as a key precursor in the synthesis of indole alkaloid analogs (Scheme 26). 

Steinhardt SE, Vanderwal CD (2009) Complex polycycUc lactams from pericyclic cascade reactions of Zincke aldehydes. J Am Chem Soc 131 7546-7547... 

Fascinating transformations starting with an electrocyclization followed by a sig-matropic rearrangement were recently described by Vanderwal. Donor-acceptor dienes known as Zincke aldehydes, available by simple aminolysis of pyridinium salts [45, 46], rearrange cleanly at temperatures of 200-220 °C to (Z)-dienes under transformation of the aldehyde portion to an amide. The reaction is commonly performed in 1,2-dichlorobenzene under microwave irradiation (Scheme 6.28). The authors consider as the first step a thermally instigated ( )- to (Z)-isomerization... 

Scheme 6.28 Isomerization of Zincke aldehyde 152 to amides of type 156 by three consecutive pericyclic reactions.

Scheme 6.29 Formation of bicyclic lactams from Zincke aldehydes (right), and side reaction to monocyclic lactams (left).

Scheme 6.30 Ketene-based mechanism for the rearrangement of Zincke aldehydes (as revealed by computation).

Cascade reactions of Zincke aldehydes (159) yield (Z)-a,, y,5-unsaturated amides (160). A computational study has discounted previous mechanistic proposals and points to a vinylketene intermediate. ... 

At the turn of the 20 century, Zincke and Konig independently discovered that pyridinium salts could be opened by amines. This process is facilitated by an electron-withdrawing group (commonly 2,4-dinitrophenyl, 53) on the pyridinium nitrogen, and the utilization of sufficiently nucleophilic primary amines can lead to re-cyclization to 55. Overall a net pyridinium A-substituent exchange occurs via an ANRORC process. If secondary amines are utilized, ring closure is prevented, and Zincke aldehydes (54) result. 

A variation of the ANRORC reaction uses an intramolecular nucleophile to open the activated heterocycle. Vanderwal accomplished a short, formal synthesis of porothramycin A and B (not depicted) via opening of the pyridinium salt with the amide nitrogen found within 59. Product 60 contains the key functionalized pyrroline of the natural product, and the expelled Zincke aldehyde was further functionalized. 

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