Natural product synthesis alkynylation

Organozinc reagents have been coupled with halides in the synthesis of dienes and other conjugated systems to form new carbon-carbon bonds such reactions have been reviewed477-479. In particular, the reaction of alkynyl zinc reagents with vinyl halides has been used in natural product synthesis, usually catalyzed by palladium complex catalysts. 

A direct and satisfactory procedure for tertiary alkyl-alkynyl coupling has been developed by Negishi and Baba, who used trialkynylaluminums readily obtainable from the corresponding alkynyllithiums and anhydrous AICI3 [92]. For instance, tris(l-hexynyl)aluminum underwent a remarkably clean reaction with 1-adamantyl bromide to produce cross-coupled product 96 in 96 % yield. It is noteworthy that the reaction enables novel geminal alkyl-alkynylation of ketones this reaction should find a considerable application in natural product synthesis (Sch. 60). 

The alkynylation reactions have been applied to polyfiuictionalized molecules (Scheme n), " and have proved to be quite useful in natural product synthesis. 

The palladium-catalyzed reaction of alkenyl-, aryl-, alkynyl- and alkylsiloxanes with aryl, alkyl, and alkenyl halides and triflates in the presence of activators is known as the Hiyama cross-coupling reaction and several reviews have been published. This chapter will present major developments and examples of recent carbon-carbon bond formation methodology and improvements as well as their use in natural products synthesis in the last few years. 

When the alkynyl substrate possesses a nucleophilic functionality, intramolecular solvomercuration reactions can sometimes be observed. These reactions, which result in the formation of a heterocycle, have been used in the total synthesis of natural products. For example, reaction of 114 with Hg(OAc)2 affords the benzofuran derivative 115, which is an important intermediate for the synthesis of various neolignans (Equation (42)).154 155... 

A microwave-driven Sonogashira coupling step is involved in the total synthesis of azaphilones, a structurally diverse family of natural products containing a highly oxygenated bicyclic core and a quaternary center. Porco and his colleagues have described the alkynylation of densely functionalized bromobenzaldehydes with... 

Nozaki-Hiyama-Kishi (NHK) reactions215,216 are well known and often employed as a useful method for the synthesis of natural products by coupling of allyl, alkenyl, alkynyl, and aryl halides or triflates with aldehydes. The organochromium reagents are prepared from the corresponding halides or triflates and chromium(ll) chloride, and are employed in polar aprotic solvents (THF, DMF, DMSO, etc.). Subsequently, it was found that nickel salts exhibited a significant catalytic effect on the formation of the C-Cr bond217,218 (Equation (19)). 

The alkynyl ketone route to pyrimidines is now well established synthetically, and an example of its use in natural products chemistry is the synthesis of several meridianin analogs, including meridinian D 697 from the indole precursor 696 <2005AGE6951>. 

Secondary and tertiary dialkylcuprates, lithium dialkenyl-, and even diphenyl-cuprates, add in very good yields to the reactive propionaldehyde diethyl acetal. The syn addition products may be trapped with a variety of electrophiles such as alkyl, alkenyl, alkynyl and aryl halides. The method has been used for the synthesis of several natural products. Substituted alkynic acetals also react with lithium dialkylcuprates in ether to furnish stable dialkenylcuprates of type (128) which do not eliminate to the corresponding alkoxy allenes (129) if the temperature is maintained below -20 C.164-179... 

Recently, Rossi et al. have applied the cross-coupling of 1-alkenylboranes with 1-alkynyl halides for the synthesis of natural products. Thus, (7 , 9Z)-7,9-dodecadien-1-yl acetate (32), the sex pheromone of Lobesia botrana, has been synthesized by the following sequence involving ... 

---