Total synthesis from simple materials

Of the many attempts at the total synthesis of lysergic acid from simple starting materials, only two have been successful (JACS 78,3087(1956), which is very complicated, and CA 74,3762 (1970), which follows). However, it is very likely that some of the intermediates in each attempt are psychedelic. In fact, this is one of... 

Methyl ketones are often directly prepared from carboxylic acids by reaction with methyllithium. Other simple alkyl ketones may also be prepared in the same fashion, making this a method that should be considered whenever these substrates are required. An important demonstration of this protocol was reported by Masamune and coworkers in their synthesis of chiral propionate surrogates (Scheme 13). The ethyl and cyclopropyl ketones are important starting materials for macrolide total synthesis and have been prepared on a large scale. The overall yield for the ethyl ketone is 65% using 3.5 equiv. of ethyllithium without protection of the hydroxy group. 

Tandem GM-RGM (see Scheme 20) can be employed for the synthesis of complex ring systems from simple starting materials. A very noteworthy example of this reaction serves as the cornerstone for the total synthethis of the natural product cyclindrocyclophane. The GM-RGM reaction of diene 182 was completely selective for formation of the head-to-tail isomer 183. The selectivity was attributed to thermodynamic control the head-to-head dimer 184 is considerably less stable. In an effort to synthesize pyrenophorin derivatives, the formation of cyclic dimers (e.g., 186) and trimers (e.g., 187) from treatment of acrylate ester-alkene derivatives (e.g., 185) with various ruthenium metathesis catalysts was examined.The product distribution was very time and concentration dependent higher concentrations favor the trimer over the dimer. 

The method of Bella is a supreme example of how the organocatalytic asymmetric Mannich reaction can facilitate the synthesis of simple pyrrolidine or piperidine alkaloids starting from achiral starting materials. Therefore, in the snbsequent paragraphs, we wish to review recent efforts made by various research groups to implement an organocatalytic asymmetric Mannich reaction as key step in the total synthesis of alkaloids, predominately derived from L-Om and n-Lys. 

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