Metathesis macrocycles

Although five- and six-membered carbo- or heterocycles are most easily formed by ring-closing metathesis, macrocyclizations with simultaneous cleavage from the support have also been successfully performed [784], Illustrative examples are listed in Table 3.44. 

Naturally, the question arises What accounts for the dramatic difference in yields between these processes Macrocyclization under kinetic control, as shown by the Staab example, is clearly not a favorable situation, as evidenced by the low yield of 14a. In contrast, it has been shown that when alkyne metathesis macrocyclization is under thermodynamic control, [n]cycles are the lowest-energy product [64]. ADIMAC of monomer 15a under the conditions shown in Scheme 6.8 generate [6]cycle 16 as the major product, and [5]cycle 17 as a minor product. Gel permeation chromatography (GPC) analysis confirmed that the oligomeric products (both linear and cyclic) that are initially formed in the reaction are consumed over time, and the [5-6]cycles are the major product upon completion. More dramatically, when polymer 15b was subjected to the same conditions, the major products... 

In 2010, Collins and coworkers [62] developed additives to aid Ru-catalyzed olefin metathesis macrocyclizations (Scheme 12.36). The macrocyclization to form strained paracyclophanes is challenging, and control of the substrate conformation is often crucial toward ensuring product cyclization. As such, the authors developed a quinolinium-based additive that interacts with the substrate, enforcing conformations conducive to ring closure, even under elevated temperatures in the presence of a competing ir-rich solvent like toluene. The macrocyclization to form the [12] and [13]paracyclophanes 121, 122, 124, and 125 or the [12]meta-cyclophane 123 were all possible through the addition of the quinolinium salt 126 to the olefin metathesis reaction mixture. No macrocyclization products... 

Shair and co-workers turned their attention to the regiochemical outcome of enyne-metathesis macrocyclizations, and they completed the biomimetic synthesis of a cytotoxic marine natural product (—)-longithorone A (204, Scheme 24.51). Biosynthetically, the natural product has been proposed originating from two [12]-paracyclophanes 205 and 206 by two Diels-Alder reactions, and thus, the authors applied enyne metathesis macrocyclization to the preparations of paracyclophanes 205 and 206. Both metathesis precmsors 208 and 210 were prepared from the common intermediate 207. The cyclization of enyne 208 in the presence of [Ru]-Ia (50mol%) in refluxing CH2CI2 under ethylene atmosphere proceeded with excellent atropdiastereoselectivity and -stereoselectivity. On the other hand, the macrocyclization of enyne 210 was less atropdiastereoselective (selective formation of the endocy-clic olefin ( /Z= 3.9 1). Nevertheless, the desired product 211 was obtained in 31% yield. In the absence of ethylene, neither macrocyclization of 208 nor 210 occurred. 

An enantioselective biomimetic synthesis of (—)-longithorone A was accomplished on the basis of the proposed biosynthesis [llj. Two [12]-paracyclophanes 25 and 26 were synthesized from common intermediate 27 by applying ene-yne metathesis macrocyclization in 42 and 31% yields, respectively. Intermolecular Diels-Alder reaction of 25 and 26 provided 32. Deprotection followed by oxidation gave 33, which spontaneously gave longithorone A via transannular Diels-Alder reaction (Scheme 6.8). 

Since then, the metathesis reaction has been extended to other types of alkenes, viz. substituted alkenes, dienes and polyenes, and to alkynes. Of special interest is the metathesis of cycloalkenes. This gives rise to a ring enlargement resulting in macrocyclic compounds and eventually poly-... 

The E/Z selectivity problem is restricted to cross metathesis and RCM leading to macrocycles (macro-RCM). Both aspects have recently been covered in reviews by Blechert et al. [8d] and by Prunet [44]. E/Z selectivity can be influenced by reaction temperature, solvent or substitution pattern of the substrate. Here, we will only discuss the influence of the precatalyst. 

Interconversion of - and Z-macrocycles in metathesis reactions proceeds via a ring-opening metathesis/ring-closing metathesis sequence thus, more... 

Transition metals have been used to complex Lewis-basic centers in metathesis substrates and to arrange the reacting olefins in such a way that cycliza-tion is facilitated. Olefin metathesis of 122, for example, proceeds with good yield to the bispyridine macrocycle 123 (Eq. 17) [115]. 

An example of the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a novel total synthesis of the macrosphelides A (209) and B (208) (Scheme 41) [100]. When the PMB-pro-tected compound 204 was examined as a metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts A or C. When the reaction was carried out using equimolar amounts of catalyst C in refluxing 1,2-dichloroethane, the cyclized product 205 was obtained in 65% yield after 5 days. On the other hand, the free allylic alcohol 206 reacted smoothly at room temperature leading to the desired macrocycle 207 in improved yield. 

The results obtained with the various metathesis substrates depicted in Scheme 44 demonstrate the lack of a stereopredictive model for the RCM-based formation of macrocycles, not only by the strong influence that may be exhibited by remote substituents, but also by the fact that the use of more reactive second-generation catalysts may be unfavorable for the stereochemical outcome of the reaction. Dienes 212a-f illustrate the influence of the substitution pattern. All reactions were performed with Grubbs first-generation catalyst A... 

Diene 265, substituted by a bulky silyl ether to prevent cycloaddition before the metathesis process, produced in the presence of catalyst C the undesired furanophane 266 with a (Z) double bond as the sole reaction product in high yield. The same compound was obtained with Schrock s molybdenum catalyst B, while first-generation catalyst A led even under very high dilution only to an isomeric mixture of dimerized products. The (Z)-configured furanophane 266 after desilylation did not, in accordance with earlier observations, produce any TADA product. On the other hand, dienone 267 furnished the desired macrocycle (E)-268, though as minor component in a 2 1 isomeric mixture with (Z)-268. Alcohol 269 derived from E-268 then underwent the projected TADA reaction selectively to produce cycloadduct 270 (70% conversion) in a reversible process after 3 days. The final Lewis acid-mediated conversion to 272 however did not occur, delivering anhydrochatancin 271 instead. 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

Thus far, chemists have been able to influence the stereoselectivity of macro-cyclic RCM through steric and electronic substrate features or by the choice of a catalyst with appropriate activity, but there still exists a lack of prediction over the stereochemistry of macrocyclic RCM. One of the most important extensions of the original metathesis reaction for the synthesis of stereochemi-cally defined (cyclo)alkenes is alkyne metathesis, followed by selective partial hydrogenation. 

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