Domino ROM/RCM

Polyether-type structures such as 6/3-38 are frequently found in bioactive compounds (e. g., maitansine). Nicolaou and coworkers [239] have developed a new, efficient approach to these compounds, which is based on a domino ROM/RCM using the second-generation Grubbs catalyst 6/3-15. Thus, the cyclobutene derivative 6/3-37 could be transformed into 6/3-38 in 80% yield (Scheme 6/3.10). 

Nonstrained heterocyclic systems can also serve as suitable substrates for domino ROM/RCM processes [11]. Scheme 2.16 illustrates extended RRM transformations of the tetraenes 38 and 40 embedding two dihydropyran moieties, which proceed with remarkable eflBciency using the ruthenium complex 2 to give the rearranged products 39 and 41, respectively, without unwanted side reactions such as dimer or macrocycle formation [11a]. 

RRM processes can also be coupled with an additional CM event Such a scenario is depicted for a norbornene derivative in Scheme 2.18 [12a]. Domino ROM/RCM of 45 with the first-generation Gmbbs catalyst 1 in the presence of terminal olefin 46 yielded the bicyclic enone 47 as a 2 1 mixture of separable ( )- and (Z)-diastereomers. Subsequently, (E -47 was successfully advanced to the cytotoxic macrolactam (-l-)-cylindramide A in a straightforward manner. The enantiopure norbornene 45 was also used in a domino RRM/CM approach to the bicyclo[3.3.0]octene core of the macrolactam geodin A [12b]. 

In a synthetic approach to artificial glutamate analogs, a domino ROM/RCM/CM reaction of oxanorbornene 50 with vinyl acetate as the co-olefin was studied (Scheme 2.20) [13d,e]. Using only 0.5mol% of the phosphine-free catalyst 4, the tricyclic product 51 was generated quantitatively and with complete control over the geometry of the exocyclic olefin. 

A flexible diversity-oriented synthesis (DOS) approach to a collection of tricyclic sultams is depicted in Scheme 2.21 [13f. The functionalized sultam scaffolds 52 and 55 embedding oxanorbornene units are readily derived by intramolecular Diels-Alder (IMDA) reactions. Domino ROM/RCM/CM transformations of these substrates using the Grubbs catalyst 2 with a set of co-olefins 53 gave rise to the desired heterocyclic systems 54 and 56, respectively, in good to very good yields. Interestingly, only one of the two epimers 55 participated in the RRM process. 

Scheme 2.24 Domino ROM/RCM/CM reaction with bicyclic dihydro-1,2-oxazine 61.

Once the domino ROM/RCM/CM reaction was optimized, different types of terminal alkenes or alkynes could be used to expand the scope of the reaction and to obtain new scaffolds [15]. This imphes, for example, blocking the RCM by introducing an alkyne (63) instead ofthe terminal alkene (64, Eq. (1), Scheme 13.14), but also modifying the position of the alkene (65) to influence the RCM and yield a tricyclic compound (66, Eq. (2), Scheme 13.14). 

An elegant directional domino ROM-RCM sequence enabled the construction of the desired tricycUc core in the presence of catalyst [Ru]-I (20 mol%) and CH2CI2 atmosphere. Four further transformations completed a concise synthesis of this complex compound in 12 steps and 17% overall yield (Scheme 11.27). 

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