Nicholas Reactions with Carboxylic Acids for the Synthesis of Macrocyclic Diolides

Abstract

[reaction: see text] We have developed a new strategy for the preparation of diolides using a cascade of Nicholas reactions. The carboxylic acid nucleophiles in these reactions are virtually unstudied participants in transformations of this type. Using this methodology, a 16-membered cobalt-complexed cyclic diyne is available in 28% yield over eight steps (an average of 85% per step). We can also easily access the uncomplexed diolide in one additional step.

Transition metals in organic synthesis: Highlights for the year 2005

“…A related reaction of a chlorobenzene 6 -ruthenium complex was used in a synthesis toward ristocetin A aglycon [1544]. (371) Nicholas-type reactions were used in synthetic applications toward macrocyclic diolides [1545] and cobalt complexed benzocycloheptynes [1546]. Diastereoselective allylations of cobalt coordinated ethynals using allylic stannanes were reported [1547].…”

The Scope and Limitations of Intramolecular Nicholas and Pauson−Khand Reactions for the Synthesis of Tricyclic Oxygen- and Nitrogen-Containing Heterocycles

“…Beyond this example, nothing was known about the scope of this reaction sequence with respect to the nature of the nucleophile in the Nicholas reaction, the size of the ring generated in the Nicholas reaction, and the size of the rings generated in the Pauson−Khand reaction. Thus, we set out to systematically address all of these issues …”

Alkyne Ligation Handles: Propargylation of Hydroxyl, Sulfhydryl, Amino, and Carboxyl Groups via the Nicholas Reaction

“…Only a few examples of carboxyl groups serving as a nucleophile in the Nicholas reaction have been reported. 21 Reaction of N -Bz-D-phenylalanine ( 9i ) with complex 6a and BF 3 OEt 2 afforded Co 2 (CO) 6 -propargyl ester 10i in 60% yield (entry 15). Reaction of 9i with complex 6c afforded a lower yield for 10i (18%, entry 16); thus, the utility of preformed propargylium salt is not necessarily general.…”

“…Carboxyl groups were also subjected to the Nicholas reaction conditions. Only a few examples of carboxyl groups serving as a nucleophile in the Nicholas reaction have been reported . Reaction of N -Bz- d -phenylalanine ( 9i ) with 6a and BF 3 OEt 2 afforded Co 2 (CO) 6 -propargyl ester 10i in 60% yield (entry 15).…”