Cyclization macrocyclization

First the protected oligopeptide is coupled with polymer-bound nitrophenol by DCC. N"-Deblocking leads then to simultaneous cycliiation and detachment of the product from the polymer (M. Fridkin, 1965). Recent work indicates that high dilution in liquid-phase cycli-zation is only necessary, if the cyclization reaction is sterically hindered. Working at low temperatures and moderate dilution with moderately activated acid derivatives is the method of choice for the formation of macrocyclic lactams (R.F. Nutt, 1980). 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

The reaction of alkenyl iodides or triflates, alkenylstannanes, and CO affords divinyl ketones[397,398]. Thus the capnellene skeleton 538 has been synthesized by the carbonylation of the cyclopentenyl triflate 536 with the alkenyltin 537[392], The macrocyclic divinyl ketone 540 has been prepared in a moderate yield by the carbonylative cyclization of 539[399]. 

The intramolecular allylation of soft carbon nucleophiles with allylic acetates as a good cyclization method has been extensively applied to syntheses of various three, four, five and six-membered rings, and medium and macrocyclic compounds[44]. Only a few typical examples of the cyclizations are treated among numerous applications. 

Intramolecular 1,4-addition is useful for macrolide synthesis. An unusual molecule of punctaporonin B (272) has been synthesized by this 1,4-addition of 271(160]. Cyclization to form the seventeen-membered ring macrolide 273 was carried out at 0.1-0.5 vi concentration[161. The choice of ligands seems to be important in the macrocyclization. The 26-membered ring model 274 for a synthesis of the ring system of tetrin A was obtained in 92% yield by using triisopropyl phosphite as a ligand[162]. 

Finally, the 1,3-dione systems prepared by Cram and Alberts deserve special note . These compounds, referred to as hexahosts are similar to the polymer-bound material illustrated as Compound 29 in Chap. 6. The synthesis is based on a methylene-bridged bis-dithiane unit. One of these may be cyclized with a polyethylene glycol, or more than one unit may be incorporated to give multiple 1,3-dione binding sites in the macrocycle. The former case is illustrated in Eq. (3.46). 

It is interesting to note that although the first examples of template effects were observed in nitrogen macrocycles (see chapter 2) no template effect appears to operate in the synthesis of 72. Richman and Atkins note this in their original report . The authors replaced the sodium cation with tetramethylammonium cations and still obtained greater than 50% yield of tetra-N-tosyl-72. Shaw considered this problem and suggested that because of the bulky N-tosyl groups, .. . the loss of internal entropy on cyclization is small He offered this as an explanation for the apparent lack of a template effect in the cyclization. 

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

Shortly after their first report of all-oxygen bridged cryptands, Dietrich, Lehn and Sauvage reported incorporation of sulfur in the strands. The experimental methods used were essentially similar to those applied in the syntheses of the parent cryptands. As in previous cases, a diacyl chloride was condensed with a diamine under high dilution conditions. In this case, however, the diamine contained sulfur atoms rather than oxygen. The synthesis of compound 5 was accomplished in two stages as illustrated below in Eq. (8.3). The first cyclization step affords the macrocyclic amine in 55% yield. The macrobicyclic product (5) is formed in 25% yield from the monocyclic diamine and the acid chloride. 

The characteristic property distinguishing macrocyclic polyamines from their linear counterparts is seen in successive protonation. One is the higher N basicity to the first proton and another is a sudden drop of N basicities in the later stages of protonation. Table 1 lists the protonation constants (Eq. 1) for the macrocyclic polyamines in comparison with the corresponding values for their linear homologues. When a linear triamine (e.g. dien) 36,37) is cyclized to, say, (9)aneN3, the basicity of the first amine increases (log Kt = 10.59 us 9.70), but the basicity of the second and especially the third amine diminish (log K2 = 6.88 vs 8.95, log K3 < 1 vs 4.25)36)... 

Scheme 1 outlines the retrosynthetic analysis of the Woodward-Eschenmoser A-B variant of the vitamin B12 (1) synthesis. The analysis begins with cobyric acid (4) because it was demonstrated in 1960 that this compound can be smoothly converted to vitamin B12.5 In two exploratory corrin model syntheses to both approaches to the synthesis of cobyric acid,6 the ability of secocorrinoid structures (e. g. 5) to bind metal atoms was found to be central to the success of the macrocyclization reaction to give intact corrinoid structures. In the Woodward-Eschenmoser synthesis of cobyric acid, the cobalt atom situated in the center of intermediate 5 organizes the structure of the secocorrin, and promotes the cyclization... 

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-... 

In developing synthetic strategies for macrocycles related to corrins, one initial choice has to be made, i.e. whether to incorporate the direct link between rings A and D or to generate it in the final cyclization step. Examples of both approaches have been reported, but syntheses in which the direct link is formed in the final cyclization are more numerous. The total syntheses of vitamin B12 by Woodward/Eschenmoser and Eschenmoser are prominent examples for the realization of both strategies. 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

Trost and coworkers137 have reported the polymer-supported palladium catalyzed cyclization of 1, l-bis(phenylsulfonyl)epoxyalkene 235 which gives cycloalkanes 236 and 237 in a 2 1 ratio (equation 143). This method has proven useful for the synthesis of macrocyclic compounds under neutral conditions without using high dilution technique. Temperature and concentrations are critical. The best results are achieved if a reaction mixture of 0.1-0.5 m is added to a preheated (at 65 °C) suspension of the catalyst. 

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. 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

In order to prove that intramolecular cyclization occurs before telechelic oligomer formation, an experiment similar to previous work by Calderonlf is performed using 14 in place of Calderon s classical catalyst system. Macrocyclic species are formed when a toluene solution of polybutadiene is exposed to this catalyst, supported by both NMR and GC data. The vinylic resonances are clearly shifted upfield from polybutadiene. GC analysis shows macrocyclic trimers and tetramer regioisomers. 

The macrocyclization of a peptide was carried out by nucleophihc substitution on a fluorobenzene by the sulfide group of the terminal cysteine of a pentapeptide [164]. The peptide 261 was prepared by standard SPPS and was cyclized under microwave irradiation at 50 °C for 10 min in DMF (Scheme 96). The yields of 262, after cleavage with TFA, were remarkably high for a macrocyclic peptide (70%) and also the resulting HPLC purity was very high. 

When disodium (Z)-l,2-dicyanoethene-l,2-dithiolate and 1,3-dibromopropane are cyclized under high dilution conditions, the desired 14-membered macrocyclic tetrathioether was isolated <96LA1005>. 

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