Ring closure macrocycle

Although the first all-sulfur macrocycles were prepared many years ago " the first systematic study of such compounds was initiated by Busch and his coworkers , who were interested in the cation binding properties of such ligands. A sequential synthesis was utilized to produce 1,4,8,11-tetrathiacyclotetradecane [tetrathia-14-crown-4 (70)] . In the first step, 1,3-propanedithiol is metallated using sodium and alkylated with 2-chloroethanol. The diol was then treated with thiourea to form the dimercapto-dithioether compound 9. The latter was once again metallated with sodium and allowed to react with 1,3-dibromopropane. The yield of 70 in the ring closure step, conducted at high dilution in absolute ethanol, was 7.5% after recrystallization. The entire sequence is illustrated in Eq. (6.8) . ... 

The palladium-catalyzed cyclization of compound 138 amply demonstrates the utility of the Stille reaction as a macrocyclization method (see Scheme 37). This efficient ring closure is just one of many examples disclosed by J.E. Baldwin and his group at Oxford.58 Interestingly, compound 138 can be employed as a stereoisomeric mixture of vinylstannanes because both stereoisomers converge on the same cyclized product. To rationalize this result, it was suggested that the configuration of the vinylstannane moiety is conserved in the cyclization, but that the macrocycle resulting from the (Z)-vinylstannane stereoisomer isomerizes to the thermodynamically favored trans product under the reaction condi-... 

Intramolecular Friedel-Crafts acylation has been observed with bonellin dimethyl ester (20).53 The reaction proceeds in contrast to corresponding porphyrins, very smoothly with concentrated sulfuric acid because the propanoic acid side chain at the sp3 center is located above the macrocyclic ring system and therefore can better fulfill the stereoelectronic requirements for the ring-closure reaction. The ring closure is accompanied by racemization in the product 21. 

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. 

A useful method to synthesize ten and fourteen-membered ring imides 346 involved an initial condensation of macrocyclic -ketoestes 343 with alkyl or aryl isocyanates and carbodiimides, respectively, in the presence of a base [68]. After a nucleophilic attack of the enolate on the isocyanate C, the resultant amide N anion 344 induced a ring closure by addition to the keto group. Then, the intermediately formed four-membered ring 345 underwent a fragmentation... 

Kruizinga, W. H., and Kellogg, R. M., Simple and high yield synthesis of macrocyclic lactones by ring-closure of caesium salts of to-halogenoaliphatic acids, J. Chem. Soc.. Chem. Com-mun.. 286-288, 1979. 

Most of the subsequent steps of tetrapyrrole synthesis are identical in plants, animals, and bacteria. The pathway includes synthesis of the monopyrrole porphobilinogen from two molecules of ALA by the action of ALA dehydratase with the elimination of two molecules of water, followed by the assembling of a linear tetrapyrrole hydroxymethylbilane from fonr molecnles of porphobilinogen, ring closure and two modification reactions of side chains. This produces the first tetrapyrrole macrocycle, uroporphyrinogen HI. Therefore, eight molecules of ALA are necessary to form one tetrapyrrole. 

The Stille reaction has been successfully applied to a number of macrocyclic ring closures.207 In a synthesis of amphidinolide A, the two major fragments were coupled via a selective Stille reaction, presumably governed by steric factors. After deprotection the ring was closed by coupling the second vinyl stannane group with an allylic acetate.208... 

Meng, Q., Hesse, M. Ring Closure Methods in the Synthesis of Macrocyclic Natural Products. 161, 107-176 (1991). 

Reactions of selected metal complexes of multidentate amines with formaldehyde and a range of carbon acids (such as nitroethane) have led to ring-closure reactions to yield a series of three-dimensional cage molecules (see Chapter 3). Condensations of this type may also be used to produce two-dimensional macrocycles (Comba et al., 1986) - see [2.20], In such cases, it appears that imine intermediates are initially produced by condensation of the amines with formaldehyde as in the Curtis reaction. This is followed by attack of the conjugate base of the carbon acid on an imine carbon. The resulting bound (new) carbon acid then reacts with a second imine in a cis site to yield chelate ring formation. 

A small number of macrocycles with an odd-number of Se atoms have been reported. Both [12]aneSe3 and [20]aneSe5 involve stepwise introduction of the Se atoms, with ring closure occurring via a high dilution cyclization of NaSe(CH2)3SeNa with TsO(CH2)3 Se(CH2)3 OTs, n = 1 or 3, respectively (Scheme 3).101... 

In the case of macrocyclic rings, the situation is better understood. In contrast to earlier statements in the literature [3a], even diene substrates devoid of any conformational pre-disposition towards ring closure turned out to be excellent substrates for macrocylization reactions catalyzed by ruthenium-carbene or -allenylidene complexes. From these investigations [30], however, a set of parameters has been deduced which turned out to be decisive ... 

Considering the facility with which dimerization products 81 and 84 are obtained, we reasoned that, in catalytic ring closure of 77, the derived dimer is perhaps initially formed as well. If the metathesis process is reversible [17b], such adducts may subsequently be converted to the desired macrocycle 76. To examine the validity of this paradigm, diene 77 was dimerized (— 85) by treatment with Ru catalyst lb. When 85 was treated with 22 mol% 2 (after pretreatment with ethylene to ensure formation of the active complex), 50-55% conversion to macrolactam 76 was detected within 7 h by 400 MHz H NMR analysis (Eq. 8). When 76 was subjected to the same reaction conditions, <2% of any of the acyclic products was detected. Although we do not as yet have a positive proof that 85 is formed in cyclization of 77, this observation suggests that if dimerization were to occur, the material can be readily converted to the desired macrolactam, which is kinetically immune to cleavage. 

In a recent study, some mechanistic aspects of this templated process have been determined quantitatively [28]. Using UV-Vis spectroscopy to monitor the kinetics of the macrocyclization reaction, it has been established that the rate of ring closure of the cationic precursor to the [ljimidazoliophane (4) is increased up to ten times in the presence of 0.04 mol/1 solution of a chloride source. The chloride stabilizes the transition state (i.e. a kinetic template) favouring the macrocyclization through hydrogen bonding. 

In the absence of a suitable template, species such as 51 are long lived in solution (due to their preference for a linear conformation) reacting intermolecularly to form larger macrocycles in preference to intramolecular ring closure. The template, on the other hand, provides the hydrogen bonding acceptor groups to... 

Challenging applications in the field of macrocyclic furans have been investigated. The major synthetic advantage is the cyclization to the furan after the macro-cyclization. This will avoid a problematic ring closure to macrocycles (to 1,3-furano-phanes) with a furan substrate ( furan latest strategy ). Test substrates demonstrated the viability of this concept [50], as shown below for the synthesis of the [8]furano-phane 91 from the macrocyclic ketone 90 (Scheme 15.22) [39]. 

For monocyclic crown ethers the data presented in Table 4 and the stability constants for glymes [43]—[46] determined by Chaput et al. (1975) can be combined to calculate the macrocyclic effect (Table 7). The data indicate that the gain in binding energy on ring closure shows the same pattern as the ion selectivity of the crown ether, being highest for Na+/15-crown-5, K+/18-... 

Since lactones are common in naturally occurring macrocycles [4], macrolactonization (Fig. 4) is an attractive way of ring closure. Many examples have... 

Ring closure of the diene in [Ru(phen)2(217)] using Grubb s catalyst generates a macrocyclic complex, the photochemical behavior of which has been studied in MeCN solution. Irradiation at >300 nm leads to the expulsion of [Ru(phen)2(MeCN)2], and quantitative regeneration of the macrocyclic complex can be achieved by heating in ethylene glycol. " ... 

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