Intermolecular reactions Nicholas reaction

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]... 

A similar Nicolas-Pauson-Khand combination was used in a synthesis of the ketone analogue of biotin 7.98, required for biochemical studies (Scheme 7.25). In this case, the Nicholas reaction was intermolecular, between allyl thiol as the nucleophile and carbocation 7.94 generated from alcohol 7.93. The Pauson-Khand reaction was then between the dicobalt complexed alkyne 7.95 and the double bond from the thiol moiety. The Pauson-Khand reaction proceeded with no stereoselectivity, and the diastereoisomers had to be chromatographically separated at a later stage. The synthesis was completed by reduction of the alkene of cyclopentenone 7.96, without using palladium-catalysed hydrogenation due to the sulfide moiety, and ester hydrolysis. 

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. 

Kann recently investigated the intermolecular Nicholas reaction with substrates on the solid phase. In a detailed study with a variety of carbon and heteroatom nucleophiles, she demonstrated that the Nicholas reaction is a useful strategy for cleaving the substrate from the resin. Enyne 35 is available upon treatment of resin-bound cobalt-alkyne eomplex 34 with allyltrimethylsilane and boron trifluoride. Generation of the requisite carbocation results in eleavage from the polymer whieh is followed by a... 

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." ... 

This solid-phase technique has made possible efficient syntheses of bi- and polycyclic systems from precursors frequently generated via Nicholas cations, (e.g. eq 60) and has been used for intermolecular reactions with methy lenecyclopropane (eq 61) and methylenecyclobutane to give spirocyclic cyclopentenone derivatives. (1) is the majorproduct when the alkyne is terminal (R = H), but only (2) was isolated when EtC2Et or Me3 SiC2Me were used. ... 

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