Natural products Sandmeyer reaction

The neurotoxic quaterpyridine natural product nemertelline was successfully synthesized by S. Rault et al. using a Suzuki cross-coupiing as the key step. The boronic acid coupling partner, required for the Suzuki reaction, was prepared by first subjecting 3-amino-2-chloropyridine to the conditions of the Sandmeyer reaction followed by a lithium-halogen exchange and trapping the lithiopyridine derivative with triisopropylborate. 

Arenediazonium salts react with cuprous chloride, cuprous bromide, and cuprous cyanide to give products in which the diazonium group has been replaced by —Cl, —Br, and — CN, respectively. These reactions are known generally as Sandmeyer reactions. Several specific examples follow. The mechanisms of these replacement reacaiions are not fully understood the reactions appear to be radical in nature, not ionic. 

Nevertheless, a more efficient approach is to attach an electron-accepting atom or radical directly to the chiral carbon atom. Chiral acids and alcohols containing chlorine at the chiral carbon atom can easily be produced from natural amino acids via the Sandmeyer reaction they are widely used in the synthesis of FLCPs [25,26,49,52-54]. A cyano group [55,56] or a perfluorinated alkyl chain [21,57] can also be attached to the chiral center. Lactic acid is a natural chiral product as well, and its derivatives are widely used as chiral terminal groups of FLCPs [27,58-61]. The search for new chiral structures with high transverse dipole moments for FLCPs has resulted in the successful application of heterocycles such as 1,3-dioxolanes [39,62] and oxiranes [63,64]. 

In earlier work, the cupric salt of 5-chlorotetrazole was rejected for practical applications due to its corrosive nature toward metals. However, it was later found that the corrosive behavior is not caused by the cupric salt itself but by chloride ions absorbed in the product from the hydrochloric acid medium in which it was prepared. This impurity is very difficult to remove by washing. It is therefore not recommended to prepare the cupric salt of 5-chlorotetrazole directly by the Sandmeyer reaction from 5-ATZ, but rather by precipitation from the sodium salt of 5-chlorotetrazole [42]. 

The power of the Sandmeyer reaction to accomplish the functionalization of aromatic rings has led to this methodology being utilized in countless natural product total syntheses. Banerjee and coworkers used a Sandmeyer bromination reaction in the synthesis of dichroanal B (22), efficiently converting aniline 20 into aryl bromide 21 in 88% yield. This particular... 

The Sandmeyer-like iodination has also found application in the synthesis of numerous natural products. Fukuyama utilized this reaction to install an aryl iodide at an early stage in his synthesis of eudistomin C (32). Diazotization of 30 followed by the addition of potassium iodide in the same pot produced aryl iodide 31 in 62% yield. 

The Sandmeyer reaction has not only been useful in the total synthesis of natural products, but the preparation of medicinally relevant compounds and heterocyclic products has been greatly simplified by this procedure. The H. Lundbeck Co. has utilized the Sandmeyer bromination in the preparation of dopamine-uptake inhibitors (38), via Sandmeyer reaction on anthranilic acid 36 to produce aryl bromide 37 in excellent yield. ... 

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