Natural product synthesis Robinson annulation

Since an annulated six-membered carbocycle is a common structural element of natural products, the Robinson annulation is an important reaction in organic synthesis. 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

Solid-phase techniques are also used for synthesis of compounds with trans-decalin motif where the Robinson annulation is used for synthesis of some natural product inspired structures such as that of 75. The protocol uses an immobilized solid phase bound Nazarov reagent that reacts with the enamine of the starting ketone under basic conditions. After cyclization the product is released from the solid phase by using TBAF at room temperature overnight. For the products 75a-c only one stereoisomer was formed (de > 98%) with modest 22-38% yields. 

The Robinson annulation has found extensive use in the synthesis of polycyclic ring systems, including steroids and other natural products containing six-membered rings. 

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