Relay metathesis

This strategy is general and allows the construction of a variety of fused rings. Extended to analogous precursors bearing two or more of these olefin metathesis relays such as (dienyl)polyalkynes, this reaction leads to the synthesis of polycyclic molecules [9] (Scheme 3). 

The example shown in Scheme 9.4 constitutes the first case of a relay cross-metathesis (relay-CM) process [7]. Reaction to give 16 is faster and more efficient for the relay-activated substrate 17 than for the parent CM partner 14. 

Scheme 9.4 The first relay cross-metathesis (relay-CM) reaction cross-coupling of donor ene-yne 17 with acceptor alkene 15.

Enyne systems are also capable of impressive multiple RRM transformations. For the first such example see Ref. [119]. The reaction of a ruthenium alkyli-dene with an alkyne produces a new vinyl alkylidene, which can participate in further intramolecular or intermolecular metathesis reactions to form fused ring systems. This has led Grubbs to designate alkynes in such systems as relays . In a noteworthy example, Zuercher et al. [ 120] constructed the four fused rings of the steroid backbone 68 in one efficient step using tandem enyne re-... 

Multiple cyclo olefinic relays are also suitable substrates to promote cascades of RCM-ROM-RCM reactions [9] (Scheme 16). Thus, W-protected polycyclic amines have been synthesized in moderate to good yields, but an increasing number of cyclopentene relays gave rise to less efficient cascade transformations. This ring rearrangement metathesis (RCM-ROM-RCM) has been extensively reported by Blechert and co-workers for its application in the synthesis of natural products [30-34]. 

Ring closing and cross metathesis allow the rapid synthesis of simple cyclic and acyclic systems. The metathesis activity that is now possible using well-defined catalysts allows for the rapid generation of complexity from simple starting materials by relay processes and combinations of metathesis steps. Many of these reactions have been recognized only recently, are now beginning to be used in complex synthetic transformations. A few of these types of reactions will be outlined here to demonstrate the power of these multistep, relay processes. In these processes, an initial metathesis step leads to a new carbene that results in further transformations of the substrate. 

In a similar way, acetylenes can serve as the relay elements in a tandem metathesis process, and such reactions result in polycyclic dienes. The starting materials are easy to prepare through standard techniques (Eq. 6.26(b)) [46]. 

Wallace DJ. Relay ring-closing metathesis—a strategy for achiev- 127. ing reactivity and selectivity in metathesis chemistry. Angew. 

Scheme 2.38 Domino relay dienyne metathesis in a formal synthesis of (—)-englerin A.

Scheme 2.38 depicts a relay dienyne metathesis transformation to afford the hydroazulene ring system [18m]. In the presence of the phosphine-free catalyst 6, substrate 103 used as an epimeric mixture underwent a completely regioselective domino cyclization due to exclusive attack of the ruthenium carbene at the terminal olefin followed by RCM with release of 2,5-dihydrofuran. Diastereomer 104 was then further elaborated to achieve a formal synthesis of the guaiane (—)-englerin A, which shows a highly selective action against renal cancer cell lines. 

Scheme 2.39 Domino relay dienyne metathesis in the total synthesis of Securinega alkaloids.

Enyne metathesis/metallotropic [l,3]-shift domino processes are also valuable for natural product synthesis [33c,d]. Reaction of substrate 168 with cis-l,4-diacetoxy-2-butene in the presence of Grubbs catalyst 2 generated the intermediate ruthenium alkinyl carbene through a relay RCM with the hberation of 2,5-dihydrofuran followed by metallotropic [l,3]-shift and terminating (Z)-selective CM with the co-olefin to yield the conjugated enediyne 169 (Scheme 2.58) [33c]. The antitumor active Panax ginseng constituent (3R,9R,10R)-panaxytriol was readily synthesized from 169 in six steps. 

Dudley and co-workers used a relay ring-closing metathesis strategy in the synthesis of (+)-dihydro-e/ /-deoxyarteannuin B, a key biogenic... 

Percy and co-workers applied a similar strategy in the synthesis of a trisubstituted cyclooctene derivative in an effort to determine the limits of relay ring-closing metathesis.Reaction of diene 315 (R = H) in the presence of 4 (three additions 10 mol %, then 5 mol % then 5 mol % over a 12-day period) and Ti(Oi-Pr)4 in refluxing dichloromethane furnished the corresponding octocycle 316 in only 24% yield. However, when a relay approach was employed, diene 317 (R = (CH2)3CHCH3) gave the... 

For reactions with more hindered termini, Hoye has developed the relay ring-closing metathesis (RRCM) approach, where a specially designed triene is used as the precursor (e.g. Scheme 2.13). ° The initial RCM step yields an intermediate carbene in which the ruthenium catalyst has been delivered to a hindered site by virtue of the intramolecular nature of the reaction this carbene then performs the desired RCM reaction. The throw-away fragment is typically a volatile unit, such as dihydro-furan or cyclopentene, although DEDAM-type units have also been utdized. ... 

Hoye TR, Jeffrey CS, Tennakoon MA, Wang J, Zhao H. Relay Ring-Closing Metathesis (RRCM) A Strategy for Directing Metal Movement Throughout Olefin Metathesis Sequences. J Am Chem Soc. 2004 126(33) 10210-10211. 

Hoye TR, Jeon J, Tennakoon MA. AUyknalonate as an Activator Subunit for the Initiation of Relay Ring-Closing Metathesis Reactions. Angew Chem Int Ed. 2011 50(9) 2141-2143. 

Ashworth IW, Miles JAL, Nelson DJ, Percy JM, Singh K. Trisubstituted cyclooctene synthesis at the limits of relay ring-closing metathesis a racemic difluorinated analogue of fucose. Tetrahedron. 2009 65(46) 9637—9646. 

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