Nicholas-Schreiber reaction

Schreiber and co-workers provide one of the most stylish examples of this approach. The successful synthesis of (T)-epoxydictymene relies on selective activation of an ethoxy group compared with an allyloxy group in the Nicholas reaction (selectivity 8.5 1) and the stereoselective PKR (Equation (37)). ... 

Later on, Schreiber used consecutively these two reactions in the key step for the synthesis of diterpene (-i-)-epoxydictimene (73), starting from natural (R)-pulegone [116,117]. This approach was built on their preliminary studies on Lewis acid mediated intermolecular Nicholas reactions [118]. They prepared functionalized enyne 70 bearing a mixed acetal. This compound was transformed into its dicobalt-hexacarbonyl complex and, in the presence of a carefully selected Lewis acid, it formed a stabilized carbocation by release of the more accessible ethyl moiety. This cation reacted intramolecularly with the allylsilane giving the central eight membered ring of the natural product... 

The high value of the Pauson-Khand reaction in the synthesis of natural products and other complex compounds has been frequently demonstrated [3]. One of the most impressive examples is the synthesis of the marine natural product (+)-epoxydictymene by Schreiber and co-work-ers [33], The synthetic strategy (Scheme 11) uses an intermolecular Nicholas reaction [34]... 

In the laboratory of S.L. Schreiber, the total synthesis of (+)-epoxydictymene was accomplished by the tandem use of cobalt-mediated reactions as key steps. The eight-membered carbocycle was formed via a Nicholas reaction, while the five-membered ring was annulated by the Pauson-Khand reaction. Several P.-K. conditions were explored and the best diastereoselectivity was observed when NMO was used as a promoter. The annulated product was isolated as an 11 1 mixture of diastereomers. 

Pauson-Khand reaction was described in Schreiber s synthesis of (-l-)-epoxydic-tymene (Scheme 4) [51,52]. The Co2(CO)g-alkyne complex first participated in a Nicholas reaction to form an eight-member ring. Subsequent Pauson-Khand cychzation provided the final 5,5-ring system. 

The most impressive use of a tandem strategy involving the Nicholas reaction in a total synthesis project is Schreiber s preparation of (+)-epoxydict5miene (61). Cobalt complexation of 58 followed by an endocyclic intramolecular Nicholas reaction with an allylsilane nucleophile yields Pauson-Khand precursor 59. Treatment of 59 with iV-methylmorpholine-iV-oxide (NMO) promotes the Pauson-Khand reaction to furnish tetracycle 60 which was ultimately converted to the target natural product 61. ... 

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