Tandem reactions Nicholas reaction

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. 

Since its discovery just over thirty years ago, the Nicholas reaction has become a highly useful tool for the organic chemistry community. Applications of the Nicholas reaction fall into four categories intermolecular reactions, endocyclic intramolecular reactions, exocyclic intramolecular reactions, and tandem reactions. For this discussion, endocyclic means that the cobalt-complexed alkyne is in the ring formed during the Nicholas reaction, while exocyclic indicates that the cobalt-alkyne complex is outside the newly generated ring. 

Several reports describe a tandem intermolecular Nicholas/intramolecular Nicholas reaction sequence for the synthesis of cyclic compounds. Green employed this strategy for the synthesis of indolophanetetrayne cobalt complexes. Dimerization of substituted indole 50 with boron trifluoride furnishes target 51 in 55% yield. Green also prepared a cobalt-complexed cycloheptyne via tandem intermolecular Nicholas/intramolecular Nicholas reactions. Boron trifluoride promotes combination of cobalt-alkyne complex 52 with allyltrimethylsilane to first yield intermolecular product 53 and then the desired intramolecular product 54. ... 

Tyrrell demonstrated a three step tandem sequence involving an intermolecular Nicholas reaction, intramolecular Nicholas reaction, and a cationic cyclization. Treatment of silyl enol ether 55 with hexacarbonyl(propiolaldehyde diethyl acetal) dicobalt and boron trifluoride provides cobalt-alkyne complex 56. Exposure of this material to tetrafluoroboric acid promotes an intramolecular Nicholas reaction to form the second six-membered ring. Alkyne decomplexation with ceric ammonium nitrate enables the final cyclization step to yield the target tricycle 57." ... 

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. ... 

Ortega, N., Martin, T, and Martin, V.S. (2006) Stereoselective synthesis of eight-membered cyclic ethers by tandem Nicholas reaction/ring-closing metathesis a short synthesis of (-l-)-cts-lauthisan. Org. Lett., 8, 871-873. 

In connection with the aforementioned reaction, Shea et al. reported the synthesis of [5,8,5]- and [5,7,5]-tricyclic oxygen-containing heterocycles via tandem Nicholas [35] and Pauson-Khand [23,24] reactions of acyclic enynes [36]. A typical Nicholas/[2 + 2 + 1] sequence is depicted in Scheme 12. 

---