Ring closing metathesis alkynes

This chapter focuses on one aspect of alkyne metathesis ring-closing alkyne metathesis (RCAM) in natural product synthesis. A brief background precedes an overview of RCAM, the catalyst systems used in RCAM-containing approaches to natural products, and a discussion of its potential as a synthetic strategy. The value... 

Ring-Closing Alkyne Metathesis (RCAM) and Alkyne... 

Fig. 3a,b Typical diyne metathesis reactions ring-closing alkyne metathesis (RCAM, a) diyne cross metathesis (ACM, b)... 

An interesting series of ring-closing alkyne metathesis reactions (RCAM) has recently been reported by Fiirstner and coworkers (Scheme 6.72) [152], Treatment of biaryl-derived diynes with 10 mol% of a catalyst prepared in situ from molybdenum hexacarbonyl and 4-(trifluoromethyl)phenol at 150 °C for 5 min led to a ca. 70% iso-... 

Scheme 6.72 Ring-closing alkyne metathesis reactions.

At the same time, Filrstner used tungsten alkyUdene complex 150 developed by Schrock for ring-closing alkyne metathesis. He compared the reactivities of tungsten alkylidyne complex 150 and Mo(CO)6-p-ClC6H40H (Table 6.4) and showed that both catalysts work well, although a higher reaction temperature is required in the case of Mo(CO)6-p-chlorophenol. 

Using this catalyst system for ring-closing alkyne metathesis, Fiirstner successfully synthesized ambrettolide and yuzu lactone from alcohol 125. " " Treatment of diyne 126a with Mo(CO)6 (5 mol%) and /i-chlorophenol (1 equiv.) in chlorobenzene at 140 °C leads to cycloalkyne 127a in 69% yield. Subsequent Lindlar reduction proceeds smoothly in a stereoselective manner to afford ambrettolide. Similarly, 126b affords cycloalkyne 127b in 62% yield. From this compound, yuzu lactone has been synthesized (Scheme 45). " " ... 

At the same time, Fiirstner and others used Schrock s tungsten alkylidyne complex 120 for ring-closing alkyne metathesis. They compared 120 with the Mo(CO)6-/>-ClC6H40H system (Table 4) in reactivity and found that... 

RCM of dienes to cycloalkenes provides a useful method for the syntheses of carbo- and heterocycles and thus has been proved to be extremely effective in total synthesis of various natural products. Usually, however, mixtures of (E)- and (Z)-olefms result. In contrast, ring-closing alkyne metathesis provides a reliable route for synthesis of both (E)- and (Z)-macrocycloalkenes in a stereoslective manner taking advantage of stereoselective partial reduction of resulting cycloalkynes. A Lindlar reduction gives (Z)-cycloalkenes, whereas a hydroboration/ protonation sequence afford ( )-cycloalkenes (Equation (23)). Recently, Trost reported an alternative procedure for the synthesis of (E)-olefins from alkynes through hydrosilylation by a ruthenium catalyst. This procedure converts cycloalkyne 130, for example, to vinylsilane 131 and then to (E)-cycloalkene 132 in a stereoselective manner (Scheme 46)7 ... 

To identify the truly active species for the alkyne metathesis, various experiments are carried out for ring-closing alkyne metathesis of diynes (Table 5). Activation of complex 140 with CH2CI2 and evaporation of all the volatiles is shown to yield Mo[N(Ar)( Bu)]3Cl 141a and alkylidyne complex 141c as major components. The former complex 141a, that is also accessible by treatment of 140 with CI2 (Equation (24)), had an equal catalytic activity (entry 6), but... 

A major drawback of alkene metathesis is lack of control over the stereochemistry of the newly formed double bond. For unstrained systems, E/Z ratios are virtually unpredictable. Alkyne metathesis, on the other hand, can always be combined with subsequent Lindlar hydrogenation, thereby giving access to stereochemically pure 2-olefins. In 1998, Ftirstner and Seidel were the first to report a ring-closing alkyne metathesis [7]. Under high-dilution conditions (0.02 m) and reduced pressure (20 mbar, removal of 2-butyne, solvent 1,2,4-trichlorobenzene (b.p. 214 °C)) the Schrock catalyst was applied to assemble macrocydic... 

An intersecting RCM is the alkyne variant called ring closing alkyne metathesis (RCAM). In this case, two alkynes, usually methyl terminated, are converted to the cycloalkyne. Unlike RCM, RCAM does not produce geometric isomers. Using this methodology, several constrained diamino-suberic analogues can be produced (Scheme 28.15).45... 

Ring-closing alkyne metathesis (RCAM) leads to alkyne macrocydes in excellent yields [36]. When combined with hydrogenation using a Lindlar-type catalyst, it is a convenient pathway to macrocydic Z-cydoalkenes. Fiirstner and coworkers utilized this strategy for numerous total syntheses of natural products [37], epothilone A being one of them [38]. 

Furstner, A., Guth, O., Rumbo, A., Seidel, G. Ring Closing Alkyne Metathesis. Comparative Investigation of Two Different Catalyst Systems and Application to the Stereoselective Synthesis of Olfactory Lactones, Azamacrolides, and the Macrocyclic Perimeter of the Marine Alkaloid Nakadomarin A. J. Am. Chem. Soc. 1999,121,11108-11113. 

Furstner, A., Grela, K. Ring-closing alkyne metathesis application to the stereoselective total synthesis of prostaglandin E2-1,15-lactone. Angew. Chem., Int. Ed. Engl. 2000, 39, 1234-1236. 

Furstner, A., Radkowski, K., Grabowski, J., Wirtz, C., Mynott, R. Ring-Closing Alkyne Metathesis. Application to the Total Synthesis of Sophorolipid Lactone. J. Org. Chem. 2000, 65, 8758-8762. 

Scheme 19. Ring-closing alkyne metathesis leaction.

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