RCM strategy

In one example of application of the RCM strategy, summarized in Scheme 107, the key intermediate 454 was obtained from 451 by sequential Wittig methylenation to 452, reductive iV-deprotection to 453, and introduction of an alkenyl chain onto the secondary amine. The RCM reaction of 454 to 455 proceeded in quantitative yield in the presence of the second-generation Grubbs catalyst <20040L965>. 

Several groups tried to access medium-sized rings (ca. 8-12 membered) with peptide-like moieties. Most prominent is the I-MCR/RCM strategy [15, 16], As shown in Scheme 11. 12-Memhered cyclic peptidomimetics were reported hy Oikawa and co-workers who used initial Ugi-4CRs performed in excellent yields, followed hy functionalization of the resulting Ugi-platform to introduce the desired alkene functionalities [65]. RCM with the second generation Hoveyda-Gruhhs... 

Scheme 11 Synthesis of confonnationally restricted cyclopeptides and cyclic peptidomimetics by the Ugi4CR/RCM strategy...

Fig. 8. Oxepines 140-146 prepared using the RCM strategy illustrated in Scheme 22.

The syntheses of l,2,3,5,6,8a-hexahydroindolizine (1) and (-)-swainsonine were successfully carried out via a ROM-RCM strategy, and final CM with ethylene to free the ruthenium. Two different synthetic routes were implemented to achieve a similar compound. In the case of l,2,3,5,6,8a-hexahydroindolizine 1, the six-membered ring was established first using RRM and in the case of (-)-swainsonine, the five-membered ring was established first. In both cases, the ring rearrangement precursors were enantiomerically pure five-membered carbocycles, which can be synthesised efficiently from racemic starting materials. 

A RCM-ROM-RCM strategy was employed as the key step to the synthesis of these alkaloids (Scheme 10). Both alkaloids can be derived from the protected bis-hydropyrrole 31 which is the ring rearranged product from the seven-membered carbocycle 32. Compound 32 can be obtained from the enantiomerically pure triol derivative 33, which in turn can be obtained from commercially available tropone 34.34... 

Snieckus reported a combination directed ortho-metalation (DoM)-RCM strategy for the synthesis of benzazepine, benzazocine, and benzannulated sulfonamide heterocycles <00SL1294> (Scheme 60). For example, the Boc-protected aniline (75) was sequentially allylated to give 76 which underwent RCM in excellent yield to give benzazepine 77. Use of similar methodology led to 78 and 79 starting from Y-methylbenzamide and p-tolylsulfonamide, respectively. 

A single example relevant to nonconjugated ring transformations has been found in the literature for the 1,4-thiazocine ring system. The sulfoxide 130 was reduced with Lawesson s reagent to form the sulfide 131 (m.p. 177-178.5 °C) (Equation 31) <2004JOC2750>. The 1,4-thiazocine 130 was synthesized via the RCM strategy (see Section 14.06.5.2), whereas the sulfide 131 could not be obtained by the same approach. 

Isomerization-RCM strategy, which was successfully applied to the synthesis of 1,4-diazocines and 1,4-oxazocines on catalysis with 77 (see Sections 14.06.3.4.1 and 14.06.4.4), afforded the benzothiazocine dioxide 139 from the sulfone 138 in high yield (Equation 33) <2004TL9171>. As for the sulfanyl compounds 134 (X = S) (Scheme 15), the substrate 138 (X = S) was inert under isomerization-RCM conditions. 

Approaches to the 1,4-dioxocines have been greatly improved during the last decade. Intermolecular condensation with the formation of two C-O bonds is an efficient route to 1,4-dioxocine ring system, particularly in the synthesis of numerous axially chiral biaryls. Intramolecular cyclization with the formation of a C-C bond, particularly by means of the RCM strategy, opened a new avenue in the synthesis of eight-membered 1,4-diheterocines with demonstrated success in the approaches to 1,4-dioxocines with a variable substitution pattern. 

Unimolecular cyclization is an important method of heteronine ring system formation. It is reviewed in this section in the order of the bond types formed. Taking into account the synthetic value of the RCM strategy and its extensive development over recent years, it is excluded from general discussion of C-C bond-formation reactions in Section... 

The thiazole-substituted homoallylic alcohol 25 (Scheme 6) is a key intermediate, not only for RCM strategies, but also for other routes. Thiazole aldehyde 4 (Chapter 3) after homologation to enal 24 (90 % yield) [ 11,20) was subjected to asymmetric allylation with allylboron and tin reagents. Interestingly 25 with identical absolute stereochemistry was synthesized by Nicolaou et al. with (+)-IpC2B(allyl) in 96 % yield and > 97 % ee [13, 20], and by Danishefsky et al. with the enantiomeric (—)-Ipc2B(allyl) in 83 % yield and > 95 % ee [11], i.e. in one case an er-... 

Compound 25, if not used in the RCM strategy, can be converted to aldehydes 26 by protection of the alcohol group and oxidative double bond cleavage (Scheme 7) [11, 13]. It is interesting to note that Schinzer et al. go the opposite way and synthesize alkene 25 from this aldehyde 26a obtained via a different route [olefination of protected (2S)-2-hydroxybutyrolactone with ArCH2P(0)(0Et)2 (3b) [21, 22] or ArCHjPBu +Cf (3c) [23]]. Nicolaou then transformed aldehyde 26b to the phosphonium salt 27 in three steps. 

An application of the RCM strategy features polycyclization reactions, wherein for instance the substrate 176 could be converted in good yield into the 3-pyrroline trimer 177 using the catalyst 178 (Equation 55) <1998JOC4291>. 

A ring-closing metathesis (RCM) strategy was utilized in the synthesis of 5-hydroxypiperidin-2-ones <03JOC2432>. Stereoselectivity is observed with optically active amino acid derivatives as starting materials. 

The RCM strategy represents an effective, reliable, and powerful approach for the construction of complex and highly functionalized medium and large rings. 

The syntheses of epothilones based on the RCM strategy were extensively investigated by the Danishefsky [142b,d], Nicolaou [143a,c], Schinzer [144a,c], and Grieco [145] groups (Fig. 9). 

The RCM strategy was applied to the synthesis of epothilone E (5c) [143i] (Scheme 83). The vinyl iodide 576, which was synthesized through C12-C13 ring-closing olefin metathesis, was subjected to the Stille coupling with 577 to afford 578. The epoxidation of the C12-C13 double bond in 578 completed the total synthesis of epothilone E (5c). 

As anticipated, the successful RCM reaction under low catalyst loading will be highly dependent on the purity of the starting material, diene ester 7. The diene ester, on the other hand, is an oil which limits purification options for purity upgrade. For robustness of the process using the RCM strategy for the macrocycle, we investigated two ester derivatives, potassium salt 44 and free acid 45. The potassium salt was conveniently prepared by treatment of diene ester 7 with powdered KOH in IPA. Upon saponification, potassium salt 44 crystallized spontaneously from the reaction media. Treatment of potassium salt 44 with 10% citric... 

Applying the mathematical model with respect to availability and availabihty gain for the structures of practical interest from the PS. Also, the time size values identification of mission time and time of reestablishment for the RCM strategy application to these equipments are estahhshed. 

The improvement of equipment maintenance strategies is an action through which major financial benefits (in the form of savings) are obtained, in the frame of PS. The application of the RCM strategy is a novel and efficient way to implement a modem and reliable maintenance system for the equipment in the PS strac-ture. The k-out-of-n type stractures are frequently used in PS. The functional structure, in the majority of electrical stations, is of this type. 

Later in the second generation of development, RCM originated and was utilised by the U.S. Department of Defence [12]. This strategy was adopted mainly by the aircraft industry and is used to determine the maintenance needed to ensure that assets fulfil their intended purpose while in operation [13]. The RCM strategy... 

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