Grubbs cyclization

Many macrocyclic lactams have potent physiological activity. Daesung Lee of the University of Wisconsin has taken advantage (Organic Lett. 2004, 6,4351) of the conformational preference of diacyl hydrazides such as 8 to prepare, by Grubbs cyclization of 8 and then again of 10, the 8-8 system 11. Exposure of 11 to Na in liquid ammonia reduced the N-N bond and opened the epoxide, to deliver macrocyclic lactam 12. 

The synthesis of (-)-cemuine 3 was concluded hy Grubbs cyclization of 17 to 3, followed again by hydrogenation. Note that there was a key difference between this cyclization and the Grubbs cyclization of 12 that led to 13, in that 17 contained a basic N, while 12 did not. For the cyclization of 12, the first generation Grubbs catalyst was sufficient, while for the cyclization of 17, the second generation catalyst was required. 

This synthesis illustrates the efficacy of the Grubbs cyclization for polycychc constniction. The approach outlined here also highlights the power of current methods for enantioselective aUylation of imines for the construction of enanfiomerically pure, and, in the context of this synthesis, diastereomericaUy pure, aminated secondary stereogenic centers. 

Grubbs applied his ring-closing olefin metathesis reaction to the synthesis of (lS,5R)-44 as shown in Scheme 67 [99]. The key-step was the cyclization of A to give C. The unreacted anti-isomer B could be recovered and equilibrated to a mixture of A and B. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

Enyne metathesis using ruthenium catalyst 52a was developed by Mori and Kinoshita [18]. When enyne 62a was treated with Grubbs s ruthenium catalyst 52a in benzene at room temperature for 22 h, the cyclized product 63a was obtained in only 13% yield (Eq. 29). It seems that the catalyst was coordinated by the diene generated in this reaction. This problem was overcome by the study of... 

The aryl radical cyclization has been successfully used for the preparation of substituted dihydrobenzo[Z)]indoline derivatives [59], An example is shown in Reaction (7.49). The diene 42 was preliminarly subjected to ring-closure metathesis using Grubbs catalyst and then treated with (TMS)3SiH and EtsB at -20 °C, in the presence of air, to provide the compound 43 with an excellent diastereoselectivity. 

Tandem cyclization of poly (ene-yne) has been achieved by Grubbs. In this reaction, a complex molecule is synthesized by one step from enyne 135 having alkenes and alkynes at appropriate positions [Eqs. (6.105)-(6.106)] " ... 

Starting from complex IX, Fiirstner developed a homobimetallic phenylindeny-lidene complex XXV (Equation 8.5), and both of these were used in the cyclization of medium-sized rings by RCM. A series of examples is presented which shows that indenylidene complexes are as good as or superior to the classical Grubbs first generation catalyst in terms of yield, reaction rate, and tolerance towards different functional groups (Scheme 8.17) [58]. 

Because of the functional group tolerance of the Grubbs catalyst 3, it will operate even with complex substrates. In the course of a total synthesis of (-)-cylisine, Giordano Lesma and Alessandra Silvani of the University of Milan reported (Organic Lett. 6 493,2004) that 5, with a free N-H, could be cyclized efficiently to 6. 

The even more spectacular cyclization of 7 to Arenastatin A 8 was reported (Tetrahedron Lett. 45 5309,2004) by Gunda Georg of the University of Kansas. In this case, the catalyst used was the first generation Grubbs catalyst, 9. 

A simple yet powerful application of the Grubbs reaction is specific homologation of a terminal vinyl group. When there is more than one alkene in the molecule, suitably disposed, one would worry about competing cyclizalion. In studies directed toward the cryptophycins, Mark Lautcns of the University of Toronto has reported (Organic Lett. 2004,6, 1883) that the second generation Grubbs catalyst 2 smoothly converts 1 to 3. The alternative cyclization product 4 is produced only in trace amounts. 

As illustrated above, free alcohols are compatible with the Grubbs reaction. In the course of a synthesis of (+)- puraquinonic acid, Derrick Clive of the University of Alberta reported (J. Org. Chern. 2004,69,4116) that the very easily oxidized alcohol 5 maintains its enantiomeric excess as it is cyclized with the catalyst 2 to give 6. 

Selectivity can sometimes be achieved by changing the Ru catalyst. James Panek of Boston University, reported (Organic belt. 2004, 6, 525) that the attempted conversion of 6 to the tetraene macrolactam core 7 of the cyclotrienins led instead to the unwanted 8. Use of the less-reactive first generation Grubbs catalyst 9 gave clean cyclization to the desired 7. 

Enyne metathesis can also be used with highly substituted substrates. Catherine Lievre of the Univcrsite de Picardie reports (J. Org. Chem. 2004,69, 3400) that enynes such as 11, readily prepared from carbohydrate precursors, are cyclized by the second generation Grubbs catalyst 2 to the enantiomerically-pure cyclic dienes, exemplified by 12. 

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