Alkene RCM

ALKENE RCM FOR THE SYNTHESIS OF AROMATIC COMPOUNDS 17.2.1 Synthesis of Substituted Benzenes... 

Alkene RCM for the Synthesis of Benzene Rings in Indoles, Carbazoles, Benzo-Fused Pyridines and Pyridones, and Benzo-Fused Imidazoles... 

As a result of the biological importance of a class of benzo-fused indole-containing compounds known as the carbazoles, many methods have been developed for their synthesis [56]. Therefore, it will come as no snrprise that alkene RCM has been nsed as a strategy for the assembly of the benzene ring moieties that form part of the carbazole nnclens. 

The use of alkene RCM has also been employed by de Koning and coworkers to construct the central benzene ring of the indolo[2,3-c]carbazole nucleus 172 found in carbazoles such as rebecca-mycin 173 [59]. Initially, conversion of the bisaldehyde 174 to 175 by means of the Wittig reaction... 

SCHEME 17.37 An alkene RCM reaction to form the benzene ring of the ferrocene-containing quinoline. (Adapted with permission from Ref. [10]. Copyright (2009) American Chemical Society). 

In 2008, Donohoe and coworkers reported the total synthesis of (—)-(Z)-deoxpukalide (1) [30], a complex marine natural product with an intriguing 14-membered carbon macrocyclic skeleton containing a trisubstituted furan moiety (Fig. 1). The key features in the synthesis involve a selective alkene RCM/aromati-zation protocol to prepare the disubstituted furan methyl ester (3) as well as a late stage RCM to furnish the butenolide moiety. Since the five-membered ring formation is more favored, the marked exomethylene functionality was intact under the alkene RCM conditions. 

In the total synthesis of the related natural product amphidinolide H (8) [34], Fiirstner et al. also utilized the late stage alkene RCM strategy for the challenging... 

Similarly, Lee and coworkers reported the total synthesis of amphidinolide X (11) through the key alkene RCM using Grubbs second generation catalyst to provide the desired natural product (11) in 74% yield, accompanied by the Z isomer byproduct in 11% yield (Fig. 4) [35]. 

Kendomycin (13) was isolated from different Streptomyces species, which showed potent antibacterial and cytostatic activities [36, 37]. Due to its challenging chemical structure and interesting biological profile, a number of impressive total syntheses have been accomplished [38]. However, all attempts to achieve 13,14-macrocyclization and formation of the desired 13,14- -olefin by alkene RCM were unsuccessful [39-41]. In 2009, Mulzer and coworkers described a novel approach to the total synthesis of kendomycin (13) via the selective alkene RCM at ClO-Cll as one of the key steps (Fig. 5) [42]. In this work, they demonstrated that RCM with Grubbs II catalyst smoothly facilitated ring closure to form the 10,ll- -olefin (15)... 

Another impressive example of macrocyclization through alkene RCM was reported by Zakarian et al. in their total synthesis of complex marine natural product (+)-pinnatoxin A (16) (Fig. 6) [43]. In this study, the remarkable formatiOTi of the 27-membered all-carbon and highly functionalized macrocycle was... 

The formation of a nine-membered ring system through alkene RCM also proved to be challenging [46]. In 2008, Hoppe et al. reported the asymmetric total synthesis of (+)-vigulariol (29), a cytotoxic and tetracyclic diterpene which was isolated from the sea pen Vigularia juncea (Fig. 10) [49]. The key step in this total synthesis involves the construction of the oxacyclononene framework by... 

Alkaloids are a large family of natural products that represent diverse and complex structures as well as important biological activities. Total synthesis of alkaloid has a rich history and has been evoking broad interest in the synthetic community [52]. Numerous strategies have been reported for the construction of polycyclic skeletons in alkaloid synthesis. In this regard, alkene RCM has been proved to be an effective means for the syntheses of a number of alkaloids of varying complexity [53]. 

One recent example was reported by Martin et al. in the first total synthesis of (+)-isolysergol (36) [54]. This synthesis was accomplished by a novel approach that features a late stage microwave-promoted, diastereoselective alkene RCM catalyzed by a chiral molybdenum catalyst to construct the desired ring system... 

The successful application of diastereoselective alkene RCM as a key step for alkaloid synthesis was also documented by two very recent examples. In 2011,... 

Mukai and coworkers reported the concise total synthesis of Melodinus alkaloid ( )-meloscine (40) [Route (a), Fig. 13], in which the final key transformation involved an alkene RCM of the triene precursor (42) in the presence of Hoveyda-Grubbs II catalyst [55], The RCM between the A(-allyl group and the top-oriented vinyl moiety exclusively occurred to generate the desired diastereomer (40) in almost quantitative yield. The extremely high diastereoselectivity could be rationalized on the basis of ring strain to favor one conformer. Shortly after this work, Curran et al. disclosed another approach to the total syntheses of ( )-epimeloscine (41) and ( )-meloscine (40) applying the same RCM protocol for the final ring formation [Route (b), Fig. 13] [56],... 

In terms of the application of selective alkene RCM for multiple ring formation, Martin et al. reported a very interesting example in their total synthesis of indole alkaloid ( )-pseudotabersonine (44) [57]. In this case, a highly functionalized tetraene substrate (45) underwent double RCMs in the presence of Hoveyda-Grubbs II catalyst to afford a mixture of two diastereomers (46) (Fig. 14). During this process the high regioselectivity for alkene RCM was achieved, which was worthy of note. 

In summary, for the last decade, selective alkene RCM has become a powerful tool for the synthesis of complex natural products. This method has been broadly applied to the construction of different ring systems including both medium-size (five- to ten-membered) and large rings. For the polyene substrate, terminal and less substituted alkenes are generally more reactive. In addition, steric effects, conformational effects as well as choice of catalysts are also key factors to achieve the selectivity. 

In the previous section we have demonstrated that alkene RCM is a powerful and broadly applicable method for the synthesis of complex natural products. However, not every diene or polyene substrate can be successfully cyclized even with the significant advantages available by variation of reaction conditimis including catalyst selection, additive use, solvent choice, and concentration, etc. In this regard, selective relay alkene metathesis provides synthetic chemists with an alternative for reviving these otherwise dead systems when such a limitation is encountered. 

Another interesting example of selective relay alkene RCM in the presence of multiple alkene and alkyne moieties was disclosed by Crimmins et al. [63]. Mucocin (60) was isolated from the leaves of Rollinia mucosa and showed potent antitumor activity [64]. Crimmins and coworkers described an enantioselective total synthesis of (-)-mucocin in 2006 (Fig. 19). In this study they highlighted a key step using selective relay alkene RCM to form the five-membered cyclic ether. 

Previous studies showed that the normal RCM reaction of simple triene (61) gave a poor regioselectivity to afford a mixture of five- and six-membered cyclic ethers. To resolve this problem, the authors tested a selective relay alkene RCM strategy, where the precursor (62) was modified to arm with an allyloxymethyl side chain. In this case, the initial ruthenium carbene species was selectively formed at the terminal alkene position of the allyloxymethyl side chain for both steric and electronic... 

Fig. 30). During this process, a high regioselectivity of two alkene RCM events was achieved. 

In 2008, Stoltz and Enquist disclosed a novel approach to the total synthesis of the related cyathin diterpenoid (—)-cyanthiwigin F (119) [80]. They applied a simultaneous alkene RCM and cross metathesis (CM) protocol to achieve the required closure of the seven-membered ring as well as elaboration of the terminal allyl group (Fig. 31). This process was effectively and selectively conducted by treating polyene (120) with Grubbs-Hoveyda catalyst (81) and a vinyl boronate species to produce the desired bicycle (121) in 51% yield. 

Fig. 34) [83]. Initially they conducted a tandem enyne/alkene RCM reaction to generate the key tricyclic diene (131). However, they observed that the yield of this cascade reaction was low, presumably due to the further decomposition of the labile diene (131) under this condition. Therefore they decided to attempt a tandem catalysis sequence and selectively hydrogenate the less-substituted alkene moiety in situ after the metathesis. As a result, the desired tricyclic product (132) was produced in 52% yield over three transformations. 

Very recently, Hoveyda and coworkers reported a very elegant total synthesis of the Aspidosperma alkaloid (-i-)-quebrachamine (139) through a highly enantioselective alkene RCM promoted by molybdenum based catalyst (141) [88, 89]. In this study... 

Fig. 37), the late-stage enantioselective alkene RCM required the closure reaction onto one of two sterically hindered vinyl groups at a congested quaternary carbon in the presence of a potentially problematic tertiary amine moiety. Through an extensive screen of chiral catalysts, gratifyingly, the desired tetracycle (142) was obtained in 84% yield and 96% ee, which allowed the completion of total synthesis of (+)-quebrachamine (139). 

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