Synthesis via RCM

Scheme 50 Epothilone synthesis via RCM between C9 and CIO dependence of chemo-selectivity on the size of the C12 substituent in metathesis substrates 244 [117]...

Figure 4.14 Polyrotaxane synthesis via RCM and ADMET polymerization of a supramolecu-lar monomer.

During the period 2001-2006, Gennari etal. pubUshed a series of accounts describing the synthesis, via RCM, of simplified eleuthesides as potential anticancer agents [104-106]. In particular, these authors recently reported a novel formal synthesis of eleutherobin 391 (Scheme 1.71) [105,106]. 

Madindoline A (7) and B (ent-8) are potent inhibitors of interleukin 6. In a total synthesis [21] that also intended to determine the relative and absolute configurations of these novel antibiotics, the densely functionalized cyclopen-tene-l,3-dione ring of 7 and 8 was elaborated via RCM of diene-diol 2 (Scheme 1). 

Scheme 51 Synthesis of novel (E)-9,10-dehydro analogs 251 of epoD, and a novel route to epoD (237d) via RCM between C9 and CIO [119]...

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

For a total synthesis of ircinal A and related manzamine alkaloids via RCM, see Scheme 25... 

Scheme 9. Synthesis of epothilone E and side-chain modified epothilones via RCM and Stille coupling, (a) 0.1 equiv of RuCl2(=CHPh)(PCy3)2 (3), CH2C12,0.004 M, 25°C, 20 h, 65% (41a 41b=1.8 l) (b) HF Py, THF,43 (84%) 44 (85%) (c) R13Sn(Aro), Pd(PPh3)4 or Pd(MeCN)2Cl2, 55-90% (d) H202, CH3CN, KHC03, 65%. Aro=aromatic (Nicolaou et al.) [20]...

Dihydropyrans can be synthesized by RCM of 4-(allyloxy)but-l-enes 241 (Equation 108). The synthesis of 3,6-dihydropyrans via RCM is vastly more common than for 3,4-dihydropyrans, as emphasized in two recent reviews C2003AGE4592, 2004CRV2199>. 

Silacycloalkenes of different size can be easily obtained via RCM of respective siladienes. Successful synthesis of 5-7-membered rings has been reported [137]. An exemplary reaction is presented in Eq. (82). 

The relative ease of ring formation from dienes decreases in the order six->seven->five-membered rings. Hoshi et al. [138] have recently reported the synthesis of a number of disilacycloalkenes via RCM of bis(allyldimethyl-silyl)substituted compounds, with the ruthenium vinylcarbene complex Cl2(PCy3)2Ru(=CHCH=CPh2) used as a catalyst. Successful formation of seven-and eight-membered rings has been achieved under mild reaction conditions. 

This section presents several of the most important advances in the synthesis of heterocycles via RCM that were made in the time period covered by this review. 

The control of alkene geometry in RCM reactions has been an area of intense research and interest since the process was first developed. While a general solution to this challenge has not yet been developed, intriguing observations of E Z control in macrocyclizations continue to be reported. For example, in the course of their studies on the synthesis of herbarumin I and II, Fiirstner and co-workers reported the selective formation of either of the two isomeric alkene products 16 or 17 via RCM of diene 15 <02JA7061> (Scheme 8). The diene 15 was transformed into the -alkene 17 using the ruthenium indenylidene catalyst (Fiirstner Metathesis Catalyst FMC, <01MI4811>) while use of the MC2 led to clean formation of the Z-isomer 16. 

The preparation of simple, cyclic 7-9 membered lactams via RCM was also reported <01SL37> (Figure 3). Organ and co-workers reported the preparation of some 8-membered lactams in their enantiospecific synthesis of inhibitors of factor Xa <02TL8177>. 

Cossy and co-workers reported the synthesis of a variety of 3-oxacycloalkenes via RCM <02TL7263> (Scheme 37). Further transformations of these compounds, such as oi-oxyalkylation and cuprate addition to the enone were also reported. 

A review of the synthesis of oxygen- and nitrogen-containing heterocycles via RCM A. Deiters, S. F. Martin, Chem. Rev. 

Kornienko s group reported the formal synthesis of cydophelitoi (1) via RCM to the diene derived from D-xylose [50]. Their s)mthetic strategy was interestingly focused on the latent plane of chirality present in D-xylose as shown in O Fig. 1, and the enantiodivergent s)mthesis of (-1-)- and (-)-cyclophelitol from D-xylose was achieved (O Fig. 1). 

As previously described, RCM is a powerful tool for the preparation of useful carbo- and heterocyclic intermediates. Almost all of the recent RCM reactions have been performed homogeneously with well-defined metal carbene complexes as catalysts. An example of the use of a heterogeneous catalyst in RCM is the synthesis of hydroazulenes such as 6 via RCM of highly functionalized diolefins (Eq. 17) catalyzed by CH3Re03/Si0i-Al703 and with heating under reflux at 80 °C [41]. 

In recent years, ring-closing olefin metathesis (RCM) has attracted organic chemists as a versatile cyclization method via carbon-carbon bond formation, and had a great impact on the synthesis of natural products [29,30]. In the syntheses of dihydropyrans of marine macrolides, allyl homoallyl ethers 28 have been cyclized to dihydropyrans 29 via RCM. This methodology has been seen in the syntheses of laulimalide by Mulzer [31,32], Crim-mins [33], and Nelson [34] (Scheme 9). 

Streptonigrin is a tetracychc aminoquinoline-5,8-dione antitumor antibiotic with high toxicity (Scheme 13). A recent synthesis via ring-closing metathesis provides a cheap and short approach to streptor rin and related compounds (13JOC12338).Two RCM approaches were used to provide the pyridine core. The second approach provided the best yields for scale-up. In this route, the catalyst was added slowly to avoid decomposition prior to the... 

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